Healthy ageing: the natural consequences of good nutrition—a conference report

Healthy ageing: the natural consequences of good nutrition—a conference report Many countries are witnessing a marked increase in longevity and with this increased lifespan and the desire for healthy ageing, many, however, suffer from the opposite including mental and physical deterioration, lost productivity and quality of life, and increased medical costs. While adequate nutrition is fundamental for good health, it remains unclear what impact various dietary interventions may have on prolonging good quality of life. Studies which span age, geography and income all suggest that access to quality foods, host immunity and response to inflammation/infections, impaired senses (i.e., sight, taste, smell) or mobility are all factors which can limit intake or increase the body’s need for specific micronutrients. New clinical studies of healthy ageing are needed and quantitative biomarkers are an essential component, particularly tools which can measure improvements in physiological integrity throughout life, thought to be a primary contributor to a long and produc- tive life (a healthy “lifespan”). A framework for progress has recently been proposed in a WHO report which takes a broad, person-centered focus on healthy ageing, emphasizing the need to better understand an individual’s intrinsic capacity, their functional abilities at various life stages, and the impact by mental, and physical health, and the environments they inhabit. Keywords Ageing · Biomarkers · Centenarians · Functional ability · Geroprotectors · Immunosenescence · Intrinsic capacity · Lifespan · Micronutrients · Minerals · Nutrition · Quality of life · Vitamins From biology to quality of life: defining ‘healthy ageing’ This is the eighth CRN-International conference report. Previous Advances in science and medicine have led to increased conference reports were published in Regulatory Toxicology and Pharmacology [139], and for the last 6 years in the European life expectancy in high-income countries. By 2050, more Journal of Nutrition [1, 15, 86, 94, 95, 136]. than one-third of the population in high-income countries is expected to be of age 60 or older [144]. As a leading * J. C. Griffiths risk factor for chronic disease, ageing is also associated with jgriffiths@crnusa.org reduced productivity and rising healthcare costs; age-related Procter & Gamble, Cincinnati, OH, USA public spending is expected to double by 2050 in many countries [158]. This combination of disease and healthcare Duke University, Raleigh-Durham, NC, USA burden has piqued societies’ interest in the topic of ageing University of Padua, Padua, Italy in recent years and led to research and medical initiatives University of Georgia, Athens, GA, USA aimed at slowing, delaying or even reversing the ageing Integrative Medicine Concepts, Tucson, AZ, USA process. To cope with these changes, the goal for societies Tufts University, Boston, MA, USA should be to optimize intrinsic capacity and functional abil- ity of individuals and populations as healthy ageing does not Creme Global, Dublin, Ireland require people to be disease-free [154]. World Health Organization, Geneva, Switzerland Nevertheless, understanding the phenomenon of ageing Amway/Nutrilite, Buena Park, CA, USA is critical to ameliorating its impact on both individuals Council for Responsible Nutrition-International, Washington, and society. Ageing has been described as “…a decline DC, USA Vol.:(0123456789) 1 3 S16 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 Fig. 1 Multifaceted aspects of Molecular ageing •Telomere length, DNA instability, epigenec alteraons Cellular •Deregulated signaling, mitochondrial dysfuncon, senescence Physiologic •Inflammaon, insulin sensivity Funconal •Sensory, balance, strength, cognive, cardiovascular Chronic disease •Heart disease, Alzheimer’s disease, diabetes, cancer, osteoporosis or loss (a “de-tuning”) of adaptation with increasing age, Researchers have recently assessed age-associated caused by a time-progressive decline of Hamilton’s forces changes in the microbiome. The population and diversity of natural selection…” [131]. However, ageing is consid- of gut microorganisms evolves with age from birth to death. ered more like the sum of its parts—a non-linear multi- Initially, there is a rapid rise in number and diversity of faceted phenomenon, that can be defined at the molecu - organisms from infancy to adulthood, followed by a pre- lar, cellular, physiologic, functional levels, and by disease cipitous decline in diversity through the elderly years [83]. state (Fig. 1). The cause for this decline is uncertain and likely multifacto- At the molecular level, ageing is perhaps most well rial. Further, it remains to be elucidated what role, if any, the defined by telomere attrition, which is believed to deter - change in microbial diversity has with the cellular, physi- mine cellular lifespan. Other molecular factors linked to age- ologic and functional changes that define the ageing process. ing include genomic instability and epigenetic alterations. The interest in ageing has progressed from understanding These, in turn, can result in declining cellular function in the its origins, mechanisms and processes, to studying how to form of altered intercellular communication, organelle dys- reduce, delay or reverse its effects, and importantly, policy function and cellular senescence [93]. These changes mani- responses that addresses older adults’ needs and rights. This fest themselves at the physiologic level resulting in chronic has led to an entire new field of research, new public health inflammation, or “inflammageing”, alterations in body com- initiatives and health and wellness consumer products col- position, energy metabolism and neuronal function [162]. lectively under the category of “healthy ageing”. Although Ageing also results in changes in sensory functions, includ- once thought of as merely the absence of disability and ing changes in taste, smell and diminished appetite [160]; chronic disease with longevity, the term healthy ageing has and changes in visual and auditory function [78]. Sarcopenia evolved to mean much more. Today, the term is meant to is a rapid age-associated decline in skeletal muscle mass and encompass social well-being and quality of life as well [84]. physical function resulting from a convergence of chronic Despite widespread interest in healthy ageing, there are dif- inflammation, hormonal changes, cellular dysfunction, poor fering definitions and interpretations of the term, e.g., “suc- diet and lack of physical activity [161]. Age-related cogni- cessful ageing” or “ageing gracefully”. Irrespective of the tive changes can also serve as precursors to dementia and term or terms used, healthy ageing has evolved to include Alzheimer’s disease [128]. In addition to cognitive disease, the intersection between avoiding and managing disease ageing also results in an increased risk for a variety of other and disability, optimizing cognitive and physical functions chronic diseases, including heart disease, diabetes and can- and engagement with life throughout the ageing years [133] cer. According to data from the US Centers for Disease Con- (Fig. 2). trol, compared to adults 45–64 years of age, those 65 and Researchers have developed indices that can be used to older have more than twice the prevalence of heart disease, predict factors, behaviors and traits that best contribute to diabetes and cancer [41]. healthy ageing. For example, Tyrovolas et al. developed a 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S17 Academy of Science, Engineering and Medicine, only caloric restriction was identified as a well-established die- tary intervention that promotes healthy ageing (specifically longevity) [112]. With a rapidly ageing global population and the accompanying increase in comorbidities, mortalities and associated social costs, there is an urgent need to iden- tify solutions including nutritional and dietary interventions that could promote healthy ageing. And despite this broad need, the ability to measure the impact of these interventions remains a major research challenge. WHO’s new mandate to measure intrinsic capacities and functional ability across the life course Society’s response to population ageing requires a vision to harness extra years of life, ensure that these years are spent in good health, and that these can be used to do what people value through-out the life course. A fundamental transforma- Fig. 2 Key factors for healthy ageing tion in policies and institutions is required to enable a cohe- sive response that celebrates diversity yet narrows health ten-point healthy ageing index, scoring attributes such as inequities, within and across countries. education, participation in social activities, number of yearly The World Health Organization (WHO) published its excursions, adherence to a healthful ‘Mediterranean diet’, first World Report on Ageing and Health in September 2015 frequency of physical activity and BMI. Elderly subjects [154], and all Member States endorsed its first Global Strat- who scored the highest on the healthy ageing index also egy and Action Plan on Ageing and Health (GSAP) in May reported using less healthcare services [143]. Other strong 2016 [155]. The Strategy represents a commitment from associations with healthy ageing include non-smoking sta- Member States and mandate for the WHO to establish part- tus, the number of social contacts, better self-perceived nerships to implement five strategic areas and reach agreed health, independent living, life satisfaction and absence of upon goals, including setting up a Decade for Healthy Age- depression [35, 64]. ing 2021–2030 aligned to Agenda 2030. One strategic area is While substantial progress has been made identifying pre- to “Improve measurement, monitoring and research” with a dictors of healthy ageing, assessing the impact of particular sub-objective to agree on ways to describe, measure, analyze interventions has proven more challenging. This is due, in and monitor healthy ageing and document a baseline across part, to the cost and difficulty of studying the long latency countries by 2020. of disability and disease, and the subjective nature of some The WHO Report and GSAP promote healthy ageing as healthy ageing predictors. Moreover, heterogeneity in the a person-centered concept, based on life course and capa- ageing processes reflects peoples’ accumulated opportuni- bility-based perspectives that can be applied to all people ties and vulnerabilities, as well as their choices and personal in all settings. Rather than a focus on morbidity or disease, values. Identifying inequalities and identifying social, eco- healthy ageing is defined as “the process of developing and nomic and other policies that can reduce unfair processes maintaining the functional ability that enables well-being in within and across countries are key to improving everyone’s older age, with functional ability determined by the intrinsic chances to optimize healthy ageing. Nonetheless, measur- capacity of the individual, the environments they inhabit and ing healthy ageing and the impact of lifestyle interventions the interaction between them.” [153]. remains an area of research focus. Metabolomics and tran- scriptomics have led to the emergence of biomarkers that may be used to assess the impact of various interventions on the process of healthy ageing [16, 109, 119]. R. Sadana is a staff member of the World Health Organization and contributed section on WHO’s new mandate to measure intrin- Clearly the role of diet and nutrition is central to the sus- sic capacities and functional ability across the life course. All listed taining of life. However, little is known about specific nutri - authors alone are responsible for the views expressed in this publi- tional interventions that most effectively promote healthy cation and they do not necessarily represent the decisions, policy, or ageing. At a recent workshop organized by the National views of the World Health Organization. 1 3 S18 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 Fig. 3 Public health framework for healthy ageing: opportuni- ties for action across the life course Functional ability (FA) comprises the health-related age and trajectories are not necessarily monotonic (that is, attributes that enable people to be and to do what they have continually decreasing). Distinguishing between IC and reason to value. It is determined by the intrinsic capacity of FA is necessary to understand if levels, distributions and the individual (i.e., the combination of all the individual’s trajectories of functioning are due to changes in the indi- physical and mental—including psychosocial—capacities). vidual or the environments they inhabit or both. It is also Moreover, ageing is not a disease. necessary to document what can be done to improve IC and Intrinsic capacity (IC) at any point in time is determined FA for individuals, groups or populations, involving differ - by many factors, including underlying physiological and ent policies, sectors and interventions. To agree on ways to psychological changes, health-related behaviors and the describe, measure, analyze and monitor IC and FA, each presence or absence of disease. These in turn are strongly concept requires further clarification, including a descrip- influenced by the environments in which people have lived tion of what are its components, pathways to optimize each throughout their lives. Environments comprise all the fac- across the life course, measurement approaches, and useful tors in the extrinsic world (understood in the broadest sense metrics to monitor and communicate progress. and including physical, social and policy environments) that WHO is pursuing a collaborative process to develop and form the context of an individual’s life. Healthy ageing is test a standardized approach to measure IC and FA that is inclusive of all older adults, in contrast to “successful age- person centered. The WHO International Classification ing” or “anti-ageing” discourses that focus on elimination of of Functioning, Disability and Health (ICF) [152] offers disease or ageing processes [107]. Moreover, broader deter- an international reference and normative framework for minants of health and intermediary determinants [135], such describing, understanding and studying health and health- as need met by health and long-term care services, are rec- related states, outcomes and determinants, that are etiology- ognized as responsible for a large part of the heterogeneity neutral and applicable to individuals and populations. This observed in older age. can inform the approach to agree on multi-domain profiles Using these concepts, the World Report proposed a pub- of IC and FA, drawing on the ICF’s universal and stand- lic health framework for action addressing healthy ageing ard dimensions of “body functions and body structures”, [9]. Figure 3 illustrates conceptually that when considering “activities”, “participation” and “contextual” factors. For the population as a whole, IC and FA can vary across the each domain, what should be measured needs to meet crite- second half of the life course. Trajectories reflect a continu- ria, such as whether this will convey useful information on ous phenomenon, and can be divided into three common a person’s or population’s current IC and FA status, whether periods: a period of relatively high and stable capacity, a this reflects a pre-condition or critical stage to optimize IC period of declining capacity, and a period of significant loss or FA in the future, or whether this is sensitive to predict of capacity. These periods are not defined by chronological potential declines or improvements. How each of these are 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S19 Fig. 4 Distribution of intrinsic capacity score for six countries, SAGE wave 1 (2007–2010), ages 50 +, both sexes actually measured—and their feasibility in clinical or com- interpersonal activities, sleep and energy, affect, and vision), munity settings—could be achieved through a range of bio- and assessed by tests and self-reported questionnaires. markers, other measured or performance tests, self-reported For people 50 years and over, Fig. 4 provides population questionnaires, or observations. Finally, each domain may representative distributions (histograms), of the compos- be assessed using several measures, then combined for each ite IC score from 0 to 100 combining information across “domain score” for a multi-domain profile of IC and FA, and each domain, with a higher score representing better IC. then be aggregated across domains, to obtain a composite Another example is reanalysis of longitudinal data drawn score for IC and FA, respectively. from the English Longitudinal Study on Ageing (ELSA) Monitoring and eventual evaluation should respond to at [32]. One analysis describes IC in five domains (vitality, least three questions: sensory, locomotor, cognitive, psychosocial), through com- monly collected biomarkers and self-reported measures over What are the levels and distribution of IC and FA glob- time; another identifies distinct trajectories of IC over time. ally and is it getting better? Finally, the WHO Model Disability Survey [27], conducted What contributes to inequalities, and whether people in nationally representative samples in Chile and Sri Lanka, have their needs and rights addressed? provides the only preliminary approach to quantifying FA What is the impact of policies and actions at different in light of hindering or facilitating aspects of the general levels (local, national, regional, global) on the average environment, such as family and social support; attitudes levels and distribution of IC and FA? of others, accessibility to information, regular use of medi- cation, personal assistance, assistive products for self-care, As there is no existing single generic instrument for mobility, seeing, hearing, work and education, facilitators at assessing IC and FA, three approaches drawing on existing home, school, work and community. data mapped to IC and FA, provide preliminary insights to Additionally, systematic efforts are needed, including rea- the first question. nalysis of other existing data, such as from the vast network Re-analyses of data collected through the WHO Study of health and retirement studies, and new research on ways on Global Ageing and Adult Health (SAGE) [134], Wave to collect data and develop a generic instrument specifically 1 (2007–2010), offer an initial attempt to measure IC in constructed to monitor IC and FA. To conclude, WHO nationally representative cross-sectional samples from all launched the International Consortium on Healthy Ageing six participating countries (China, Ghana, India, Mex- Metrics and Research in March 2017 and it has identified ico, Russia, South Africa). IC is described through eight work packages to build up standards on healthy ageing data, domains (mobility, self-care, pain and discomfort, cognition, measures, and metrics by 2020. Members include academic 1 3 S20 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 institutions, other UN and international bodies, non-govern- an exceptionally long life [126]. Centenarians in Georgia ment organizations, as well as other collaborative networks, are diverse in terms of race/ethnicity, socio-economic fac- e.g., the UN City group on age and age-disaggregated data. tors, living situation (living in the community vs. nursing Measuring the change, we collectively want to see is part of homes), and many other factors [125]. Nutrition was exam- the fundamental transformation needed across societies to ined through food frequency questionnaires and biomarkers enable healthy ageing. of nutritional status in the serum and in post-mortem brain Given the vast literature, evidence and recommendations tissue. on nutrition and older adults, three discussion questions to Compared to Georgia centenarians in nursing homes, consider: those residing in the community were more than twice as likely to be able to eat without help and to receive most of 1. How can the concepts of IC and FA take stock of the their nourishment from typical foods [69]. However, those importance and “natural consequences of good nutri- residing in nursing homes had significantly higher exposure tion” for healthy ageing—to optimize IC and FA across to all food groups examined, including dairy, meat, poultry the life course—particularly the second half of life? and fish, eggs, green vegetables, orange/yellow vegetables, 2. Likewise, in the construction of multi-domain profiles of citrus fruit or juice, and oral liquid supplements. These find- IC and FA—that are etiology-neutral/person-centered, ings suggest that nursing homes provide environmental sup- what should be included and how should these be meas- port in the form of nourishment for centenarians. ured? What can be measured in clinical settings, in com- Serum biomarkers of vitamin B12, vitamin D and carot- munity settings or where people live? enoid status also were assessed. Adequate vitamin B12 sta- 3. What existing research and monitoring efforts and tools tus was significantly positively associated with being Afri- can provide opportunities to re-analyze data and or test can American vs. white, taking dietary supplements with new data collection approaches by 2020? B-vitamins, and not having atrophic gastritis [71], indicating that predictors of vitamin B12 status are related to race/eth- Key references: [151–153]. nicity, intake from supplements, and preservation of gastric function. Vitamin D status (serum 25-hydroxyvitamin D) in Geor- Cross‑cultural approaches to biomarkers gia centenarians was similar to that for the US population of for healthy ageing older adults [70], but much higher than centenarians in Italy where vitamin D fortification of foods is uncommon [121]. Definitions of healthy ageing continue to evolve. The WHO It is possible that widespread use of dietary supplements recently conceptualized a public-health framework for and fortification of the food supply in the US accounts for healthy ageing that considers physical health, mental health, the similar vitamin D status among Georgia centenarians environment, and environmental support [154]. Priorities for compared to the US population. In these Georgia centenar- action that can help achieve healthy ageing under this frame- ians, vitamin D status was higher among whites vs. African work include aligning health systems to the older population Americans, those taking dietary supplements with vitamin they now serve, developing systems of long-term care, creat- D, and those assessed in the summer or fall [70]. Seasonal ing age-friendly environments, and improving measurement, variation in vitamin D status suggests that very long-lived monitoring and understanding. This framework can also be people may retain some ability to synthesize vitamin D used to support the rapidly growing population of the very in the skin. Also, higher vitamin D status among Georgia old, such as centenarians who are aged 100 and older [140]. centenarians was significantly associated with higher grip This presentation elaborated on WHO’s framework in two strength, a measure of functional ability [50]. ways among centenarians: (1) nutrition as an environmen- Post-mortem concentrations of brain lutein in the subset tal support to healthy ageing and (2) examination of cross- of centenarians without dementia were significantly and pos- cultural differences and similarities between centenarians itively associated with a range of cognitive measures [68]. residing in Tokyo, Japan and Georgia, USA, in subjective In contrast, there were few associations of alpha-tocopherol measures of well-being, physical health, and social health. with cognitive function [68]. In summary, several biological and environmental factors Nutrition in long‑lived Georgians (USA) are associated with vitamin status throughout life includ- ing among centenarians. These factors include race/ethnic- The Georgia Centenarian Study (USA) has been ongoing ity, use of dietary supplements, food fortification, certain since 1988 and seeks to understand how centenarians live foods, and season in the case of vitamin D. Also, measuring, longer and to identify specific biological, psychological, monitoring, understanding, and modifying the nutritional sociological, and nutritional characteristics that support environment are essential for long-lived people. 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S21 or reversed, producing increases in healthy lifespan [39, 75]. Cross‑cultural differences in Japan vs. Georgia (USA) Translation of these therapies, called “geroprotectors” [110], to extend human healthspan is increasingly plausible [92, The subset of participants who were cognitively intact were the focus of these cross-cultural comparisons among cen- 113, 114]. A barrier to translation is the challenge of meas- uring changes in the rate of human ageing. tenarians in Japan compared to Georgia [111]. There were marked differences in demographic characteristics between Unlike worms, flies, and mice, humans live too long to observe complete lifespans within individual studies. Age- the Japanese and Georgia centenarians such as the percent living at home (93 vs. 80%, respectively) and living alone related disease and disability typically develop over the second half of the human life course, a period spanning (5 vs. 40%, respectively). Differences in several indices of health were also observed. Compared to the Japanese, the decades. Interventions that modify biological processes of ageing to prevent age-related disease are, therefore, needed Georgia centenarians had significantly worse cognitive func- tion and better physical function (activities of daily living), relatively early in life, before age-related disease becomes established [49, 108]. True tests of the effectiveness of such but fewer chronic diseases and better vision and hearing. The Philadelphia Geriatric Center Morale Scale was interventions will require decades of follow-up. To establish proof of concept for such long-term studies, measurements used to measure subjective well-being. Georgia centenar- ians reported higher scores on well-being (satisfaction with are needed that allow tests of a candidate therapy’s potential to slow the rate of human ageing over shorter intervals [12, social relations and psychological comfort). However, these cultural differences in well-being were attenuated after con- 73]. Measurements to quantify biological processes of ageing trolling for predictors such as sociodemographic factors and health resources. Regression analyses revealed that health could be implemented to test putative geroprotective effects of interventions over the short term. Measurements taken resources (cognitive function, hearing problems, and activi- ties of daily living) were strong predictors of well-being in before, during, and at the conclusion of an intervention could be used to estimate how that intervention might change the both countries. Social resources (living with others) were strongly associated with one dimension of well-being (atti- rate of age-dependent deterioration in system integrity, providing a simple test of whether the intervention showed tude toward one’s ageing) only among the Japanese cen- tenarians. These findings support the existing lifespan and promise to extend healthspan. Measurements to quantify biological processes of ageing are now being developed. The cross-cultural literature, indicating that declines in health impose certain limitations on adaptive capacity in oldest-old most promising combine multiple sources of information, e.g., from clinical parameters or gene expression and DNA age irrespective of cultures, and that social embeddedness is valued in Eastern cultures [111]. methylation measurements [74]. Initial epidemiologic stud- ies of these algorithm-based biomarkers of ageing indicate These cross-cultural comparisons of centenarians sug- gest that the environment differs among individuals and promise [74]. For example, so-called “epigenetic clocks” composed of dozens or hundreds of methylation marks have among cultures, especially regarding living alone or living in a nursing home, which are both high among the Georgian been shown to predict mortality in multiple studies [24]. Research is needed to test if these new ageing biomarkers compared to the Japanese centenarians. Also, findings in the Georgia centenarians suggest that nutrition may be a modi- can inform evaluations of candidate therapies to slow ageing and extend healthspan [13]. fiable environmental factor for physical function (vitamin D) and cognition (lutein). Studies are ongoing to examine Work by Belsky et al. [10–13] has focused primarily on measures of biological ageing derived from indices of organ associations of cognitive and brain health with additional nutrients in the Georgia centenarians, such as vitamin K, system functioning, including blood chemistries, blood counts, and organ system tests such as blood pressure, lung docosahexaenoic acid (DHA), and other fatty acids [68]. function, and cardiorespiratory fitness measurements. This work has yielded four main findings. First, consistent with Quantification of biological ageing: theories of biological ageing, organ systems throughout the body show age-dependent declines in integrity even among implications for clinical trials of interventions to slow ageing and extend young healthy people in their 20s and 30s. Moreover, the rate of this decline is correlated across different organ systems healthy lifespan and is variable between individuals. Thus, measurement of the rate of biological ageing in relatively young people as Interventions to extend healthy lifespan or “healthspan” are needed. Accumulating evidence suggests molecular changes the average rate of decline in integrity across organ systems is possible [11]. Second, young people whose bodies exhibit that occur with ageing are among the root causes of age- related disease and disability [80, 93]. Experiments with a faster rate of biological ageing measured in this way have worse physical functioning, as measured by tests of strength, animals show that these molecular changes can be slowed 1 3 S22 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 balance, and motor coordination, and show evidence of early Food consumption surveys are also used to evaluate the cognitive decline, as measured from changes in cognitive benefits and safety of potential supplementation and forti- test performance between childhood and midlife. They also fication strategies, as well as to inform businesses on con- report being in worse health and are rated as looking older sumer intakes, dietary impact of products and ingredients, by others [11]. Third, people with early-life characteristics as well as research and development decisions. In addition, associated with shorter healthy lifespan, including exposure the data are used for monitoring food safety via food expo- to childhood poverty and child maltreatment, poor health in sure assessments to additives, pesticides and contaminants. childhood, and low childhood cognitive function and deficits When analyzing and modelling those specific topics, it is in self-control evidence a faster rate of biological ageing of importance to have access to individual food diaries, [10]. Fourth, the rate of biological ageing measured from detailed and quality food composition or chemical data, decline in the integrity of multiple organ systems is slowed demographic, anthropometric and biomarker data. Meth- by caloric restriction, an intervention established to extend odologies for assessment of food and supplement intake healthy lifespan in animals [12]. This last study observed vary widely, however, there is a view to harmonizing them changes in the rate of biological ageing over the relatively within the European Union (EU) [2]. short term of a 2-year intervention trial. Even though the acceleration in data generation pre- Critically, Belsky et al. [10–13] observed consistent find- sents opportunities, gaps in availability or access, unfit- ings for multiple approaches to quantify biological ageing for-purpose data, lack of specific information and out- from organ system function data using their own longitudi- of-date data remain an outstanding challenge for public nal-change “Pace of Ageing” approach and cross-sectional health nutrition research. To overcome such problems, methods that compare research participants to reference data sources including market research data, online tools populations to quantify their biological age [82, 90] or their and platforms to gather data more efficiently, as well as homeostatic dysregulation [29]. These methods, which can the construction of new models combining complemen- be implemented using standard blood chemistry panels and tary data from various sources of origin can be promising other data routinely collected in clinical studies, suggest new alternatives. possibilities for studies to evaluate interventions that may Models such as the Compiled European Food Consump- affect the rate of ageing. In theory, these measures of biolog- tion Database [116] and the Global Expanded Nutrient Sup- ical ageing may be more sensitive than individual disease- ply (GENuS) Model [138] extrapolate consumption using endpoint measures, which focus on more extreme outcomes. existing databases. The Compiled European Food Consump- Instead, biological ageing measures are designed to capture tion Database estimates the consumption of the European subtle, organism-wide shifts in physiological integrity. They population using European Food Safety Authority (EFSA) may thus provide an interesting avenue for studies of nutri- comprehensive summarized intake statistics [98] and simu- tional interventions. lating 29 days of intake distributions for 40,000 individuals using 36 clusters of age groups and gender having similar diets. A limitation is that the database contains no estimates Public health nutrition in the data of nutrient intakes and no breakdown by country. Also due age: opportunities, pitfalls, and future to the applied methodology, some outliers may be over- or perspectives underestimated. The GENuS model uses Food and Agricul- tural Organization (FAO) food balance sheets, production To study healthy ageing, data-driven tools and models can and trade data combined with nutrient composition tables to be used to quantify nutrition and health in a population. calculate the nutrient supply across 175 nations, 26 demo- The value of good data can be stressed as it plays a key graphic groups and 225 food categories. The database, how- role in today’s data age, including the use of secondary data ever, does not assess consumption of foods at the individual sources. To assess intakes at a population and subpopulation level and nutrient availability is overestimated. Examples of level, the data collected need to be of high quality, while ongoing efforts to gather up-to-date and more harmonized keeping in mind time, cost, participant burden and other data on food consumption are the EU menu [2] and the Inter- factors. The opportunity to analyze specific demographics, national Dietary Data Expansion (INDDEX) project [28], including vulnerable groups from a nutritional standpoint, is but whether the databases will be accessible and how they of great importance when trying to address healthy ageing. can be used remain to be seen. Food consumption surveys provide extensive information. The use of large datasets and mathematical models They enable the assessment and monitoring of health and to assess and define optimal dietary changes in specific nutritional status of specific demographics, to inform healthy populations can generate valuable insights and opportuni- eating guidelines and to reduce diet-related chronic diseases, ties for public health nutrition strategies and food product which all have a part to play in healthy ageing. development. 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S23 Consumption of bioactive compounds can have beneficial 2025, the number of US individuals > 65 will increase by and/or adverse health effects; however, intakes of those com- 50% [150]. Globally, currently 686 million people (12%) pounds are not routinely assessed in populations. As part of the are over 60. By 2050, it is predicted that there will be nearly European Commission (EC)-funded BACCHUS, ‘Beneficial as many people aged > 60 as children under 15. In many effects of bioactive compounds in humans’ project, national countries, life expectancy of age 60 is now at least a third food consumption data were linked to bioactive composition more than what it was in the mid-twentieth century [55]. data. To estimate intake distributions and to account for vari- Interestingly, the over-80 group is projected to be the fast- ability of bioactive concentrations, a probabilistic intake mod- est growing subset in this over-65 trend, which was 14% elling approach was applied [5, 124]. in 2012, and is predicted to be at 20% in 2050 [150]. This In the EC-funded ODIN project on vitamin D entitled Food- represents a major demographic shift with significant public based solutions for optimal vitamin D nutrition and health health and socio-economic impact. Advances in science have through the life cycle; EC Contract 613977 [117], national greatly increased lifespan; however, at the same time, new food consumption surveys and a standardized vitamin D data- and developing challenges, such as sarcopenia, cardiovascu- base were combined to assess vitamin D nutrition. Incremen- lar disease, obesity, diabetes, dementia, macular degenera- tal food fortification scenarios, such as enrichment of animal tion, cataracts, and emerging infections, as well as the costs food sources (meats, eggs, fish and dairy products) were then associated with these conditions are on the rise, impact- applied to ensure the safe increase of vitamin D intakes across ing the health and functional lifespan of older adults while the population distribution and prevent deficiency. In addition, diminishing their ability to be fully contributing members safety across European countries was assessed using available of their communities. data on consumption [98] and a worst-case scenario approach Accumulating evidence, however, indicates that poor due to the lack of individual data [123]. health in late life is not inevitable. Contrary to the previously Another example examined new food products and their held belief that increased risk of diseases and disability with impact on health outcomes, such as blood pressure and car- advancing age results from inevitable, as well as genetically diovascular events, by assessing individual data on food determined intrinsic ageing processes, more recent studies consumption combined with intake models. This study by indicate that many of the usual ageing characteristics are Dainelli et al. [31] looked at the shift in intakes of potas- due to lifestyle and other modifiable factors and are not una- sium-fortified milk powder and consecutively the health voidable consequences of ageing itself [42, 51, 66]. Thus, impact via replacing milk consumption with the fortified developing strategies to increase “health span” or the years product in adults above the age of 45. of “successfully ageing” for older adults becomes critical— As part of the overall Healthy Ireland initiative [53], the socially, and economically. Irish food industry is proactively contributing to healthier Studies across species show that ageing is associated choices and product reformulation, but progress is not with dysregulated immune and inflammatory responses, assessed regularly when looking at consumption. To quan- which may contribute to many age-related diseases includ- tify the impact of voluntary food reformulation efforts on ing cancer, infection, cardiovascular diseases, diabetes, Alz- Irish consumers, probabilistic intake assessments were heimer’s disease and osteoporosis. The immune system is performed using Irish national food consumption surveys comprised of different cell types that engage in a complex (IUNA) in combination with industry data on reformulated series of interactions to defend the host against invading product composition and market share data [60–63, 122]. pathogens. These interactions, under normal conditions, are Combining databases and probabilistic intake models well-orchestrated so that a temporary upregulation in inflam- represents a great opportunity for informing public health matory responses needed to eliminate the pathogen is subse- strategies, including healthy ageing. The impact of dietary quently diminished and controlled. With ageing, the normal changes via using and modelling databases can provide pow- “checks and balances” of the immune response is impaired, erful information for government and industry; however, creating a state of chronic inflammation (hyperactivity of available and fit-for-purpose databases, as well as the tools parts of the immune system involved in innate immune and expertise to exploit such data remain a challenge. response) on one hand, and hypoactivity of the cell-mediated immunity, particularly T cells, on the other (Fig. 5). This dichotomy presents a challenge in devising effec- Public health implications tive interventions to prevent/treat age-related changes of the of immunosenescence: role of nutrition immune response. Recent evidence, however, suggests that both the hyper- and hypo-activity of immune response asso- Since January 1, 2011, every day for the next 20 years, ciated with ageing might be governed by some of the same roughly 10,000 Americans will celebrate their 65th birth- molecular/biochemical aberrations that might be responsive day. The US Census Bureau projects that between 2005 and to nutritional intervention. 1 3 S24 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 particularly the case when the focus is moved from clinical- Ageing based studies, where QoL is a traditional outcome of clinical or nutritional intervention, to the broader context of public Inflammation health. Public health implications of nutrition and QoL in the older stages of life are of paramount importance, being interconnected to all of the most prominent issues, from (1) multi-comorbidities enhanced by poor diet and nutrient de- fi T cell function ciencies, (2) polypharmacy as a consequence of the former situation and as a sign of improper approaches to healthy lifestyles, to (3) social aspects such as meal sharing with friends or families and (4) economic aspects, such as food Fig. 5 Ageing is associated with dysregulated immune and inflam- insecurity. matory responses exhibiting increased inflammation on one hand and Not only has better diet in older adults been shown to be decreased T-cell-mediated function on the other hand associated with significantly higher physical and emotional QoL scores [147] and with better functional status [45], but A significant portion of the global older population have the whole life satisfaction in older adults is impacted by nutritional problems exhibited as both under-nutrition (e.g., nutritional adequacy [79]. The definition of healthy age- micronutrient deficiencies such as B vitamins, vitamin C, ing itself includes diet quality and eating habits as essential E, D, Se, Zn, Ca, and Fe) and over-nutrition (i.e., obesity); components [121], with immediate consequences on hard often existing together [81]. These age-associated nutritional outcomes, such as overall and disease-specific mortality problems provide opportunities and challenges in developing [89]. Diet quality, which is mainly defined in terms of proper interventions that could reduce inflammation while improv - nutrient variety and adequate caloric intake, is, however, ing host defense against infection. Strategies include sin- rarely met in older adults, mostly because of the aforemen- gle nutrient interventions, e.g., vitamin E [20, 46, 48, 52, tioned issues. In particular, intake of fruits and vegetables, 56, 99, 103, 105], vitamin B6 [106], zinc [6–8, 43, 100, which provide a wide variety of different micronutrients and 126], fish oils [102, 104, 159], or whole food such as wolf- bioactive compounds, are sub-optimally consumed by older berry [38, 127, 145, 146] and pre-and probiotics [40, 87]. In people, with no improvement over the past decade. Sup- addition, calorie restriction in both animal and humans has plementation has been advocated as a valid remedy to ame- been shown to reduce inflammation and improve immune liorate diet quality challenges in older adults, most often in response [3, 101, 115, 149]. These studies provide strong a very cost-effective way. In a recent review (unpublished) evidence that appropriate nutritional intervention could opti- on the impact of reported use of the active administration of mize the immune and inflammatory responses in older adults any dietary supplement (vitamins, minerals, herb or botani- leading to improved resistance to chronic and infectious cal compounds, amino acids, dietary substances, concen- diseases. These interventions, particularly started earlier in trates, metabolites, constituents or extracts), the analysis of life, could have significant public health implications for 83,350 subjects showed reported supplement use was associ- older adults. However, success has been curbed due to the ated with a significant reduction in mortality risk for cancer lack of adequate information on specific nutritional needs of (pooled estimated HR 0.93, 95% CI 0.88–0.99) and stroke older people. As a result, older people of a wide age range (pooled estimated HR 0.97, 95% CI 0.95–0.99). A marked from 60 to 100 and with varied genetic and socio-economic impact on stroke mortality was noted for Ginkgo biloba- backgrounds are included in studies without appreciation containing supplements (HR 0.59, 95% CI 0.37–0.93), for heterogeneity of their nutritional status, which in turn, Selenium + Coenzyme Q10-containing supplements (HR reduces the effectiveness of any given intervention. Address- 0.46, 95% CI 0.33–0.64) and vitamin B (HR 0.75, 95% CI ing this gap, would expedite development of efficient and 0.62–0.91). Alternatively to a single-component analysis of cost-effective nutritional strategies to improve quality of life the effects of supplementation on health, a recent review on in older adults. Papers screened on PubMed & EmBase for trials with sample A public health perspective on nutrition size greater than 200 subjects (aged at least 50  years old, defined as and its impact on quality of life healthy or without specific diagnosis, or with most common ageing diseases—cardiovascular diseases, age-related macular degeneration, dementia or diabetes). Outcomes considered were at least one of the Despite the obvious connection existing among ageing, following outcomes: all causes mortality, CV death, major CV events nutrition and quality of life (QoL) in older adults, a sys- (composite endpoint, stroke, myocardial infarction, revascularization, tematic investigation in the field is lacking [37]. This is etc.), and cancer. 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S25 Fig. 6 Distribution of expected number of stroke events without (gray bars) and with concentrates supplementation (smoothed curves). Data are Monte Carlo microsimulations referred to the decade 2015–2025 for US fruit and vegetables concentrates and their potential impact Supplementation could thus be seen as a cost-effective solu- on risk reduction for major health events [47] showed a tion to overcome behavioral obstacles typical of older age strong inverse relationship between reported consumption yet ensuring proper intake of most relevant nutrients. and major chronic disease, in particular coronary heart dis- ease and stroke (unpublished) (Fig. 6). Thus, the potential gain in terms of events avoided due to a better nutrition, via Life in the margins: the health impact supplementation, in older adults, suggests a potential reduc- of micronutrient insufficiency tion of public health expenditure. The same simulation scenario as in the previous case Micronutrient deficiencies are common in older adults shows indeed that a significant number of cases were avoided around the globe [157]. Numerous factors can limit the (approximately 9,965,819 (95% CI 643,567–25,202,911)), ability of elders to access and consume nutrient-dense attributable to nutrient supplementation (in people aged 65 foods, such as declining income, impaired mobility, poor years or more) (Table 1). In this scenario, fostering vitamin oral health, altered taste and smell, loss of appetite, lack of consumption via fruits and vegetables or by supplementa- food variety, changes in cognition and diminished vision. tion is an essential component for promoting healthy ageing. The greatest burden of chronic disease is borne by older adults, which by their very nature can lead to a disruption of the immune system, changes in metabolism, and impact inflammatory mediators, which can increase the body’s The review focused on seven “concentrates” (juice plus—J+, need for specific micronutrients. Medications used to treat orange juice fruit and vegetable juice—FV juice, fruit juice, cherry juice, Jerusalem artichoke juice, Artichoke leaf juice). These com- chronic disease can be nutrient wasting, causing significant pounds were analyzed in terms of their impact on measurable physi- declines in the status of micronutrients vital for well-being ological outcomes (total cholesterol, homocysteine, systolic blood and health. pressure, body mass index and tumor necrosis factor alpha), widely While frank nutrient deficiency states are well-known accepted in literature as risk factors for cardiovascular NCDs. Lit- erature review results provided input for Markov chain simulation (e.g., rickets, scurvy, pellagra), there is a growing body of model, calibrated on US 2015–2025 general population, population evidence showing that less than optimal biochemical levels with metabolic syndrome and hypertension. Effect of concentrates are associated with impaired cognitive function, cardiovas- was thus simulated by linking the direct effect of each concentrate on cular disease, cancer, poor bone health, eye disease and other a clinical surrogate with the effect of the same surrogate on stroke. 1 3 S26 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 Table 1 Simulated savings in US due to the usage of supplements Age–class No supplementa- Beta-carotene C E B9 ACE tion Overall Health 65–84 403.294 (174.347; 402.078 (174.267; 360.849 399.338 391.886 (171.277; 392.184 (172.092; Care Expenditure 887.958) 871.077) (168.383; (173.627; 844.23) 821.755) (US$) 785.064) 851.128) 85 + 92.353 (40.706; 91.796 (40.695; 85.913 90.63 90.522 (40.667; 89.342 (40.482; 203.283) 199.223) (40.187; (40.564; 193.803) 192.82) 167.567) 202.015) Numbers are billions US$. Computation referred to US population 2016 and extrapolated to the decennium 2015–2025 on the estimates based on Medical Expenditure Panel Survey [54] conditions that are common in older populations [22]. The of appetite, joint pain, depression, loss of taste and smell, focus of this presentation was to examine the prevalence, cognitive impairment, and dementia [118]. Both patients and impact and risk factors for several key micronutrients in the clinicians may assume that some of these signs and symp- ageing population. toms are simply the result of ageing. Screening for B12, including methylmalonic acid (a more sensitive indicator of Vitamin B12 B12 status) should be considered in any patient experiencing these symptoms, who are vegetarian or vegan, or with long- The risk for vitamin B12 deficiency increases with age. term metformin and/or PPI use [85, 96, 120]. Using data from the National Health and Nutrition Examina- tion Survey (NHANES), 6.9% of US adults aged 51–70 years Vitamin D and 15% of those over 70 years are B12 deficient [17]. Simi- lar findings were reported in Germany, with 27.3% of peo- Optimal vitamin D status is necessary for the absorption of ple aged 65–93 having deficient serum B12 levels [30]. The calcium and phosphate required to preserve mineral homeo- decline in gastric acid secretion that occurs with advancing stasis and bone health, as well as maintaining skeletal mus- age can make it difficult to absorb food-bound B12 in meat, cle performance [26]. While hypovitaminosis D is common poultry, seafood, dairy, and eggs. For this reason, the Insti- worldwide, it is more common and severe in elders [21] tute of Medicine recommends adults over the age of 50 get due to both environmental and biological factors. Impaired their B12 from fortified foods and/or supplements [59]. mobility and residential care often limit time spent outdoors The risk for low B12 in elders may be further com- and decreased synthesis of vitamin D in the skin makes it pounded by the widespread use of proton pump inhibitors difficult to maintain adequate levels even with sun exposure. (PPI) and histamine H2 blockers, which dramatically inhibit As ageing advances, intestinal resistance to 1,25(OH)2D gastric acid secretion and the absorption of B12 [96]. A 2015 impairs the uptake of calcium and a decline in renal func- meta-analysis found an 80% increased risk of deficiency tion reduces vitamin D activation [33]. Thus, the Institute of after 10 months of regular PPI use [72]. Many older adults Medicine recommends that adults over age 70 take ≥ 800 IU are prescribed a PPI to prevent gastric bleeding secondary per day (20 µg) of vitamin D3 and increase calcium from to the use of aspirin, anticoagulants, and/or non-steroidal 1000 mg per day to 1200 mg per day for women over age anti-inflammatories. These drugs are used in the manage- 50 years and men over 70 years [58]. ment of cardiovascular disease and pain, two conditions that Osteoporosis is a silent disease and a major health con- disproportionately affect older adults. cern given the ageing of the global population. It is respon- The risk for diabetes also increases with age. Of the sible for more than 8.9 million fractures annually worldwide 30 million Americans with type-2 diabetes, 12 million are [67]. Falls are a major cause of fractures and are more com- over the age of 65 [76]. Metformin, a medication commonly mon in older adults. Roughly 30 % of people over age 65 prescribed for the treatment of type-2 diabetes, reduces fall annually, with 10–15% of these falls resulting in frac- serum B12 levels and worsens diabetes-associated neuropa- ture [77]. Sixty percent of those who fell in the previous thy [120]. Many patients taking metformin are not monitored year, will fall again [141]. Seventy-five percent of hip, spine or screened for B12 status [23]. It is not uncommon in clini- and distal forearm fractures occur among those 65 years or cal practice to see a 70-year old patient on both long-term older [97]. Fragility fractures are associated with decreased metformin and PPI. quality of life, increased disability, more frequent hospital B12 deficiency can lead to difficulty walking, tingling/ admission and an increased risk of mortality [88]. While a numbness in hands and feet, fatigue, shortness of breath, loss multimodal approach is important for fall protection, vitamin 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S27 D supplementation alone, or in combination with calcium, plague older adults: type 2 diabetes, metabolic syndrome, has been shown to significantly reduce the risk of falling in chronic inflammation, high blood pressure, atherosclerotic elders [142]. vascular disease, sudden cardiac death, osteoporosis, and A meta-analysis that included eight studies with 30,970 colon cancer [129]. Almost half (48%) of the US popula- participants conducted by the National Osteoporosis Foun- tion consumed less than the recommended amount of dietary dation found that calcium plus vitamin D supplementation magnesium in 2005–2006; down from 56% in 2001–2002 resulted in a statistically significant 15% reduced risk of total [130]. The Canadian Health Measures Survey (2012–2013), fractures and 30% reduced risk of hip fractures [148]. This found that 9.5–16.6% of Canadian adults had a serum mag- translates into large economic savings, decreased morbidity nesium below the lower reference cut-off [14]. and mortality, and improved quality of lives. Evidence from epidemiological studies, randomized con- Given the data showing the beneficial effects of vitamin trolled trials, and meta-analyses suggest an inverse associa- D on falls and fracture, it is somewhat surprising that many tion between magnesium and cardiovascular disease [132]. patients who experience a fragility fracture are not recom- A 2013 meta-analysis that included 16 studies with more mended vitamin D. In one Italian study, most patients over than 313,000 participants found higher blood levels of mag- age 65 years who had a hip fracture (98.2 and 88.3% in 2011 nesium (per 0.2 mmol/L increment) were associated with a and 2015, respectively) did not receive vitamin D supple- 30% lower risk of cardiovascular disease [34]. Magnesium mentation at the time of the fracture and only 30–35% were supplementation reduces plasma C-reactive protein (CRP) receiving vitamin D supplements 1 year after the fracture concentrations in those with levels > 3  mg/dL, which is [26]. This is unfortunate as supplementation may reduce the indicative of inflammation and an increased risk for cardio- number of subsequent fractures, enhance muscular strength, vascular disease [137]. and improve balance [25]. Magnesium is important for maintaining healthy blood Numerous medications can lead to low bone mineral den- pressure and supplementation (365–450 mg/day) has been sity and an increased risk for fracture. Statins may cause a shown to significantly lower blood pressure in those with decline in vitamin D levels and lead to smaller increases in insulin resistance, prediabetes, and other chronic diseases serum 25(OH)D concentration even with supplementation [36]. This is important given that some anti-hypertensive [18, 19]. Anticonvulsant medications accelerate vitamin D medications (e.g., thiazide diuretics) can cause hypomagne- metabolism and increase the risk for fracture [65]. Gluco- semia, decreasing their effectiveness and increasing the risk corticoids, aromatase inhibitors and androgen deprivation for heart arrhythmias [91]. treatments all significantly increase the risk for osteoporosis As mentioned previously, diabetes is a major public and fracture. The American Geriatrics Society recommends health concern, with the global prevalence increasing from against the use of PPIs for longer than 8 weeks in older 4.7% in 1980 to 8.5% in 2014, and continuing to rise [156]. adults, except in high-risk patients, due to the potential risk Insulin resistance has been shown repeatedly to decrease of bone loss, fractures and risk of Clostridium difficile infec- magnesium levels and diabetics with low magnesium show a tion [4]. more rapid disease progression and an increased risk for dia- Clinicians should assess 25(OH)D levels in those with betes-related complications. A vicious forward feeding cycle risk factors for low vitamin D, correct any deficiency, and is created. Magnesium supplementation has been shown to maintain serum levels ≥ 30 ng/mL (75 nmol/L), as recom- improve glucose metabolism and insulin sensitivity in those mended by the Endocrine Society [57]. Vitamin D supple- with type-2 diabetes [44]. mentation beyond what is currently recommended is often Certain medications can cause a decline in magnesium. necessary to correct an underlying deficiency. While the safe The Food and Drug Administration has mandated a warning upper limit for vitamin D supplementation has been set at that long-term use PPI can cause dangerously low magne- 4000 IU per day for most adults [58], clinicians generally sium levels and thiazide diuretics, often a first line treatment use 50,000 IU per week or 6000 IU per day for 8 weeks, or for hypertension, can cause a decline in magnesium, as well longer, to correct deficiency states [57]. as potassium. Dietary calcium intake should be assessed with a goal of While serum magnesium is a useful screening tool, red 1000–1200 mg per day. Patients with chronic kidney dis- blood cell magnesium testing is considered more accu- ease should be closely monitored for vitamin D and calcium rate and should be considered in patients with risk fac- intake to avoid elevated serum calcium. tors for hypomagnesemia. Magnesium supplementation (200–500 mg per day) is generally considered safe; however, Magnesium clinicians should be cautious in those with diminished renal function. Low magnesium intakes and low serum magnesium lev- Given the ageing of the global population, it is impera- els are associated with many of the chronic conditions that tive that health policy advocates, governmental officials, 1 3 S28 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 clinicians and the public be made aware of the importance of increasing age…” Although the nine subject-matter experts micronutrients in overall health, particularly in older adults. provided their insights and in some cases, laboratory-derived Clinicians must have more training in how to identify poten- data points applicable to healthy ageing, it is also evident tial nutrient dec fi iencies and what testing is most appropriate that the surface has been barely scratched and that many for determining the status of specific nutrients. We urgently additional definitions, end-points, markers of ageing can need more research to determine the “optimal” reference be proposed, and that there are likely many well-conceived range for key micronutrients in older adults, as well as mak- possible lifestyle options that can be modified to achieve ing nutrient testing more widely available, more economi- improved health and optimize the lifespan. One theme that cal, and reimbursed by insurance and government programs. resonates through this entire report is that ageing is NOT Otherwise, we will continue to see many older adults living a disease. The phrase “successful ageing” does not do jus- in the margins, when it comes to their micronutrient status. tice to the inclusive opportunity that drive an individual to While the consumption of nutrient-dense food is the foun- achieve their optimal lifespan. Quality is equally important dation for obtaining nutrients, it is simply not enough in to the quantity of life years deemed appropriate for each certain cases, such as vitamin D. Given the key role that individual, given both controllable and uncontrollable calcium and vitamin D play in maintaining bone and skel- impacting parameters. Most of the presenters either called etal muscle health, nutrient status should be more rigorously out terms such as functional ability and intrinsic capacity, evaluated by the clinician and supplementation more widely or in their oral and written contributions drew tangential recommended. With a fragility-related fracture occurring points to the health-related attributes that enable a lifespan every 3 s, this inexpensive approach should become part value option affected by the underlying physiological and of standard practice in primary and geriatric care for the psychosocial factors, health and lifestyle-related behaviors management of osteoporosis [67]. and the presence/absence of disease and rapidly-developing The widespread use of prescription drugs for the manage- decrements. Finally, the mental picture of a life course can ment of many chronic health conditions can also make it be intuitively described with adjustments in internal (genet- difficult to maintain adequate levels of specific nutrients. PPI ics) and external (environment) elements over the lifespan drugs are one of the most commonly prescribed medications affecting the slope and trajectory of a life, a progress towards and are also available over-the-counter in the United States. death that is overlaid by debilitating life stages associated The long-term use of these drugs can increase the risk of with perceptions of unhealthy and unforgiving “old age”. fracture, cause magnesium levels to plummet, and interfere Acknowledgements This conference report summarizes the presenta- with B12 absorption, as well as increasing the risk of C. tions and outcomes of the meeting entitled “Healthy Ageing: he Natural difficile infection. With the increasing prevalence of type-2 Consequences of Good Nutrition” held on December 2, 2017, in Berlin, diabetes, we will continue to see an increase in prescriptions Germany. The event was organized by the Council for Responsible Nutrition-International (http://www.crn-i.ch). The opinions expressed, for metformin, a drug known to deplete vitamin B12. While herein, are those of the authors; this conference report is not a consen- these medications can be incredibly beneficial, many older sus statement; therefore, some authors may not agree with all opinions adults are taking these drugs long term without any monitor- expressed. R. Sadana is a staff member of the World Health Organiza- ing of micronutrient status. Many clinicians are unaware of tion and contributed the section on WHO’s new mandate to measure intrinsic capacities and functional ability across the life course. All the potential for nutrient wasting associated with medication listed authors alone are responsible for the views expressed in this use and simply are not looking for it. publication and they do not necessarily represent the decisions, policy, Given that even marginal micronutrient status can or views of the World Health Organization. The section on WHO’s adversely affect muscle, joint, and eye health, as well as the new mandate to measure intrinsic capacities and functional ability across the life course draws on work by several groups and individuals, immune, cardiovascular and neurological systems, there is including John Beard, Somnath Chatterji, Alarcos Cieza, Islene Araujo an urgent need for better evidence-based guidelines, educa- de Carvalho, Ana Posarac, Jean-Pierre Michel, Jothees Amuthavalli, tion and communication with public health officials, medical Jinkook Lee, Matilde Leonardi, Gerald Stucki, Alana Officer and Anne professionals and the public. Margriet Pot. Compliance with ethical standards Conclusion Conflict of interest D.W. Belsky, D. Gregorio, M.A. Johnson, T. Low Dog, S. Meydani, S. Pigat, R. Sadana, A. Shao and J.C. Griffiths had The annual CRN-International Scientific Symposium and their travel expenses reimbursed by CRN-I. D. Marsman, T. Low Dog, subsequent conference report is continuing to explore and S. Pigat, and A. Shao are employees of their respective companies, refine scientific content related to optimal nutrition and a Procter & Gamble, Integrative Medicine Concepts, Creme Global, healthy lifespan. It is apparent that they are related, most and Amway/Nutrilite. T. Low Dog is also president of Dr. Low Dog’s Apothecary and an employee of Health Lifestyle Brands. J.C. Griffiths likely with the former affecting maximal length and achiev - is an employee of CRN-International. None of the authors declares ing a lessening of the “…decline or loss of adaptation with 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S29 any conflict of interest in providing their solely scientific opinion for (2017) Eleven telomere, epigenetic clock, and biomarker-com- this review. posite quantifications of biological aging: do they measure the same thing? 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Healthy ageing: the natural consequences of good nutrition—a conference report

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Chemistry; Nutrition
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Abstract

Many countries are witnessing a marked increase in longevity and with this increased lifespan and the desire for healthy ageing, many, however, suffer from the opposite including mental and physical deterioration, lost productivity and quality of life, and increased medical costs. While adequate nutrition is fundamental for good health, it remains unclear what impact various dietary interventions may have on prolonging good quality of life. Studies which span age, geography and income all suggest that access to quality foods, host immunity and response to inflammation/infections, impaired senses (i.e., sight, taste, smell) or mobility are all factors which can limit intake or increase the body’s need for specific micronutrients. New clinical studies of healthy ageing are needed and quantitative biomarkers are an essential component, particularly tools which can measure improvements in physiological integrity throughout life, thought to be a primary contributor to a long and produc- tive life (a healthy “lifespan”). A framework for progress has recently been proposed in a WHO report which takes a broad, person-centered focus on healthy ageing, emphasizing the need to better understand an individual’s intrinsic capacity, their functional abilities at various life stages, and the impact by mental, and physical health, and the environments they inhabit. Keywords Ageing · Biomarkers · Centenarians · Functional ability · Geroprotectors · Immunosenescence · Intrinsic capacity · Lifespan · Micronutrients · Minerals · Nutrition · Quality of life · Vitamins From biology to quality of life: defining ‘healthy ageing’ This is the eighth CRN-International conference report. Previous Advances in science and medicine have led to increased conference reports were published in Regulatory Toxicology and Pharmacology [139], and for the last 6 years in the European life expectancy in high-income countries. By 2050, more Journal of Nutrition [1, 15, 86, 94, 95, 136]. than one-third of the population in high-income countries is expected to be of age 60 or older [144]. As a leading * J. C. Griffiths risk factor for chronic disease, ageing is also associated with jgriffiths@crnusa.org reduced productivity and rising healthcare costs; age-related Procter & Gamble, Cincinnati, OH, USA public spending is expected to double by 2050 in many countries [158]. This combination of disease and healthcare Duke University, Raleigh-Durham, NC, USA burden has piqued societies’ interest in the topic of ageing University of Padua, Padua, Italy in recent years and led to research and medical initiatives University of Georgia, Athens, GA, USA aimed at slowing, delaying or even reversing the ageing Integrative Medicine Concepts, Tucson, AZ, USA process. To cope with these changes, the goal for societies Tufts University, Boston, MA, USA should be to optimize intrinsic capacity and functional abil- ity of individuals and populations as healthy ageing does not Creme Global, Dublin, Ireland require people to be disease-free [154]. World Health Organization, Geneva, Switzerland Nevertheless, understanding the phenomenon of ageing Amway/Nutrilite, Buena Park, CA, USA is critical to ameliorating its impact on both individuals Council for Responsible Nutrition-International, Washington, and society. Ageing has been described as “…a decline DC, USA Vol.:(0123456789) 1 3 S16 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 Fig. 1 Multifaceted aspects of Molecular ageing •Telomere length, DNA instability, epigenec alteraons Cellular •Deregulated signaling, mitochondrial dysfuncon, senescence Physiologic •Inflammaon, insulin sensivity Funconal •Sensory, balance, strength, cognive, cardiovascular Chronic disease •Heart disease, Alzheimer’s disease, diabetes, cancer, osteoporosis or loss (a “de-tuning”) of adaptation with increasing age, Researchers have recently assessed age-associated caused by a time-progressive decline of Hamilton’s forces changes in the microbiome. The population and diversity of natural selection…” [131]. However, ageing is consid- of gut microorganisms evolves with age from birth to death. ered more like the sum of its parts—a non-linear multi- Initially, there is a rapid rise in number and diversity of faceted phenomenon, that can be defined at the molecu - organisms from infancy to adulthood, followed by a pre- lar, cellular, physiologic, functional levels, and by disease cipitous decline in diversity through the elderly years [83]. state (Fig. 1). The cause for this decline is uncertain and likely multifacto- At the molecular level, ageing is perhaps most well rial. Further, it remains to be elucidated what role, if any, the defined by telomere attrition, which is believed to deter - change in microbial diversity has with the cellular, physi- mine cellular lifespan. Other molecular factors linked to age- ologic and functional changes that define the ageing process. ing include genomic instability and epigenetic alterations. The interest in ageing has progressed from understanding These, in turn, can result in declining cellular function in the its origins, mechanisms and processes, to studying how to form of altered intercellular communication, organelle dys- reduce, delay or reverse its effects, and importantly, policy function and cellular senescence [93]. These changes mani- responses that addresses older adults’ needs and rights. This fest themselves at the physiologic level resulting in chronic has led to an entire new field of research, new public health inflammation, or “inflammageing”, alterations in body com- initiatives and health and wellness consumer products col- position, energy metabolism and neuronal function [162]. lectively under the category of “healthy ageing”. Although Ageing also results in changes in sensory functions, includ- once thought of as merely the absence of disability and ing changes in taste, smell and diminished appetite [160]; chronic disease with longevity, the term healthy ageing has and changes in visual and auditory function [78]. Sarcopenia evolved to mean much more. Today, the term is meant to is a rapid age-associated decline in skeletal muscle mass and encompass social well-being and quality of life as well [84]. physical function resulting from a convergence of chronic Despite widespread interest in healthy ageing, there are dif- inflammation, hormonal changes, cellular dysfunction, poor fering definitions and interpretations of the term, e.g., “suc- diet and lack of physical activity [161]. Age-related cogni- cessful ageing” or “ageing gracefully”. Irrespective of the tive changes can also serve as precursors to dementia and term or terms used, healthy ageing has evolved to include Alzheimer’s disease [128]. In addition to cognitive disease, the intersection between avoiding and managing disease ageing also results in an increased risk for a variety of other and disability, optimizing cognitive and physical functions chronic diseases, including heart disease, diabetes and can- and engagement with life throughout the ageing years [133] cer. According to data from the US Centers for Disease Con- (Fig. 2). trol, compared to adults 45–64 years of age, those 65 and Researchers have developed indices that can be used to older have more than twice the prevalence of heart disease, predict factors, behaviors and traits that best contribute to diabetes and cancer [41]. healthy ageing. For example, Tyrovolas et al. developed a 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S17 Academy of Science, Engineering and Medicine, only caloric restriction was identified as a well-established die- tary intervention that promotes healthy ageing (specifically longevity) [112]. With a rapidly ageing global population and the accompanying increase in comorbidities, mortalities and associated social costs, there is an urgent need to iden- tify solutions including nutritional and dietary interventions that could promote healthy ageing. And despite this broad need, the ability to measure the impact of these interventions remains a major research challenge. WHO’s new mandate to measure intrinsic capacities and functional ability across the life course Society’s response to population ageing requires a vision to harness extra years of life, ensure that these years are spent in good health, and that these can be used to do what people value through-out the life course. A fundamental transforma- Fig. 2 Key factors for healthy ageing tion in policies and institutions is required to enable a cohe- sive response that celebrates diversity yet narrows health ten-point healthy ageing index, scoring attributes such as inequities, within and across countries. education, participation in social activities, number of yearly The World Health Organization (WHO) published its excursions, adherence to a healthful ‘Mediterranean diet’, first World Report on Ageing and Health in September 2015 frequency of physical activity and BMI. Elderly subjects [154], and all Member States endorsed its first Global Strat- who scored the highest on the healthy ageing index also egy and Action Plan on Ageing and Health (GSAP) in May reported using less healthcare services [143]. Other strong 2016 [155]. The Strategy represents a commitment from associations with healthy ageing include non-smoking sta- Member States and mandate for the WHO to establish part- tus, the number of social contacts, better self-perceived nerships to implement five strategic areas and reach agreed health, independent living, life satisfaction and absence of upon goals, including setting up a Decade for Healthy Age- depression [35, 64]. ing 2021–2030 aligned to Agenda 2030. One strategic area is While substantial progress has been made identifying pre- to “Improve measurement, monitoring and research” with a dictors of healthy ageing, assessing the impact of particular sub-objective to agree on ways to describe, measure, analyze interventions has proven more challenging. This is due, in and monitor healthy ageing and document a baseline across part, to the cost and difficulty of studying the long latency countries by 2020. of disability and disease, and the subjective nature of some The WHO Report and GSAP promote healthy ageing as healthy ageing predictors. Moreover, heterogeneity in the a person-centered concept, based on life course and capa- ageing processes reflects peoples’ accumulated opportuni- bility-based perspectives that can be applied to all people ties and vulnerabilities, as well as their choices and personal in all settings. Rather than a focus on morbidity or disease, values. Identifying inequalities and identifying social, eco- healthy ageing is defined as “the process of developing and nomic and other policies that can reduce unfair processes maintaining the functional ability that enables well-being in within and across countries are key to improving everyone’s older age, with functional ability determined by the intrinsic chances to optimize healthy ageing. Nonetheless, measur- capacity of the individual, the environments they inhabit and ing healthy ageing and the impact of lifestyle interventions the interaction between them.” [153]. remains an area of research focus. Metabolomics and tran- scriptomics have led to the emergence of biomarkers that may be used to assess the impact of various interventions on the process of healthy ageing [16, 109, 119]. R. Sadana is a staff member of the World Health Organization and contributed section on WHO’s new mandate to measure intrin- Clearly the role of diet and nutrition is central to the sus- sic capacities and functional ability across the life course. All listed taining of life. However, little is known about specific nutri - authors alone are responsible for the views expressed in this publi- tional interventions that most effectively promote healthy cation and they do not necessarily represent the decisions, policy, or ageing. At a recent workshop organized by the National views of the World Health Organization. 1 3 S18 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 Fig. 3 Public health framework for healthy ageing: opportuni- ties for action across the life course Functional ability (FA) comprises the health-related age and trajectories are not necessarily monotonic (that is, attributes that enable people to be and to do what they have continually decreasing). Distinguishing between IC and reason to value. It is determined by the intrinsic capacity of FA is necessary to understand if levels, distributions and the individual (i.e., the combination of all the individual’s trajectories of functioning are due to changes in the indi- physical and mental—including psychosocial—capacities). vidual or the environments they inhabit or both. It is also Moreover, ageing is not a disease. necessary to document what can be done to improve IC and Intrinsic capacity (IC) at any point in time is determined FA for individuals, groups or populations, involving differ - by many factors, including underlying physiological and ent policies, sectors and interventions. To agree on ways to psychological changes, health-related behaviors and the describe, measure, analyze and monitor IC and FA, each presence or absence of disease. These in turn are strongly concept requires further clarification, including a descrip- influenced by the environments in which people have lived tion of what are its components, pathways to optimize each throughout their lives. Environments comprise all the fac- across the life course, measurement approaches, and useful tors in the extrinsic world (understood in the broadest sense metrics to monitor and communicate progress. and including physical, social and policy environments) that WHO is pursuing a collaborative process to develop and form the context of an individual’s life. Healthy ageing is test a standardized approach to measure IC and FA that is inclusive of all older adults, in contrast to “successful age- person centered. The WHO International Classification ing” or “anti-ageing” discourses that focus on elimination of of Functioning, Disability and Health (ICF) [152] offers disease or ageing processes [107]. Moreover, broader deter- an international reference and normative framework for minants of health and intermediary determinants [135], such describing, understanding and studying health and health- as need met by health and long-term care services, are rec- related states, outcomes and determinants, that are etiology- ognized as responsible for a large part of the heterogeneity neutral and applicable to individuals and populations. This observed in older age. can inform the approach to agree on multi-domain profiles Using these concepts, the World Report proposed a pub- of IC and FA, drawing on the ICF’s universal and stand- lic health framework for action addressing healthy ageing ard dimensions of “body functions and body structures”, [9]. Figure 3 illustrates conceptually that when considering “activities”, “participation” and “contextual” factors. For the population as a whole, IC and FA can vary across the each domain, what should be measured needs to meet crite- second half of the life course. Trajectories reflect a continu- ria, such as whether this will convey useful information on ous phenomenon, and can be divided into three common a person’s or population’s current IC and FA status, whether periods: a period of relatively high and stable capacity, a this reflects a pre-condition or critical stage to optimize IC period of declining capacity, and a period of significant loss or FA in the future, or whether this is sensitive to predict of capacity. These periods are not defined by chronological potential declines or improvements. How each of these are 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S19 Fig. 4 Distribution of intrinsic capacity score for six countries, SAGE wave 1 (2007–2010), ages 50 +, both sexes actually measured—and their feasibility in clinical or com- interpersonal activities, sleep and energy, affect, and vision), munity settings—could be achieved through a range of bio- and assessed by tests and self-reported questionnaires. markers, other measured or performance tests, self-reported For people 50 years and over, Fig. 4 provides population questionnaires, or observations. Finally, each domain may representative distributions (histograms), of the compos- be assessed using several measures, then combined for each ite IC score from 0 to 100 combining information across “domain score” for a multi-domain profile of IC and FA, and each domain, with a higher score representing better IC. then be aggregated across domains, to obtain a composite Another example is reanalysis of longitudinal data drawn score for IC and FA, respectively. from the English Longitudinal Study on Ageing (ELSA) Monitoring and eventual evaluation should respond to at [32]. One analysis describes IC in five domains (vitality, least three questions: sensory, locomotor, cognitive, psychosocial), through com- monly collected biomarkers and self-reported measures over What are the levels and distribution of IC and FA glob- time; another identifies distinct trajectories of IC over time. ally and is it getting better? Finally, the WHO Model Disability Survey [27], conducted What contributes to inequalities, and whether people in nationally representative samples in Chile and Sri Lanka, have their needs and rights addressed? provides the only preliminary approach to quantifying FA What is the impact of policies and actions at different in light of hindering or facilitating aspects of the general levels (local, national, regional, global) on the average environment, such as family and social support; attitudes levels and distribution of IC and FA? of others, accessibility to information, regular use of medi- cation, personal assistance, assistive products for self-care, As there is no existing single generic instrument for mobility, seeing, hearing, work and education, facilitators at assessing IC and FA, three approaches drawing on existing home, school, work and community. data mapped to IC and FA, provide preliminary insights to Additionally, systematic efforts are needed, including rea- the first question. nalysis of other existing data, such as from the vast network Re-analyses of data collected through the WHO Study of health and retirement studies, and new research on ways on Global Ageing and Adult Health (SAGE) [134], Wave to collect data and develop a generic instrument specifically 1 (2007–2010), offer an initial attempt to measure IC in constructed to monitor IC and FA. To conclude, WHO nationally representative cross-sectional samples from all launched the International Consortium on Healthy Ageing six participating countries (China, Ghana, India, Mex- Metrics and Research in March 2017 and it has identified ico, Russia, South Africa). IC is described through eight work packages to build up standards on healthy ageing data, domains (mobility, self-care, pain and discomfort, cognition, measures, and metrics by 2020. Members include academic 1 3 S20 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 institutions, other UN and international bodies, non-govern- an exceptionally long life [126]. Centenarians in Georgia ment organizations, as well as other collaborative networks, are diverse in terms of race/ethnicity, socio-economic fac- e.g., the UN City group on age and age-disaggregated data. tors, living situation (living in the community vs. nursing Measuring the change, we collectively want to see is part of homes), and many other factors [125]. Nutrition was exam- the fundamental transformation needed across societies to ined through food frequency questionnaires and biomarkers enable healthy ageing. of nutritional status in the serum and in post-mortem brain Given the vast literature, evidence and recommendations tissue. on nutrition and older adults, three discussion questions to Compared to Georgia centenarians in nursing homes, consider: those residing in the community were more than twice as likely to be able to eat without help and to receive most of 1. How can the concepts of IC and FA take stock of the their nourishment from typical foods [69]. However, those importance and “natural consequences of good nutri- residing in nursing homes had significantly higher exposure tion” for healthy ageing—to optimize IC and FA across to all food groups examined, including dairy, meat, poultry the life course—particularly the second half of life? and fish, eggs, green vegetables, orange/yellow vegetables, 2. Likewise, in the construction of multi-domain profiles of citrus fruit or juice, and oral liquid supplements. These find- IC and FA—that are etiology-neutral/person-centered, ings suggest that nursing homes provide environmental sup- what should be included and how should these be meas- port in the form of nourishment for centenarians. ured? What can be measured in clinical settings, in com- Serum biomarkers of vitamin B12, vitamin D and carot- munity settings or where people live? enoid status also were assessed. Adequate vitamin B12 sta- 3. What existing research and monitoring efforts and tools tus was significantly positively associated with being Afri- can provide opportunities to re-analyze data and or test can American vs. white, taking dietary supplements with new data collection approaches by 2020? B-vitamins, and not having atrophic gastritis [71], indicating that predictors of vitamin B12 status are related to race/eth- Key references: [151–153]. nicity, intake from supplements, and preservation of gastric function. Vitamin D status (serum 25-hydroxyvitamin D) in Geor- Cross‑cultural approaches to biomarkers gia centenarians was similar to that for the US population of for healthy ageing older adults [70], but much higher than centenarians in Italy where vitamin D fortification of foods is uncommon [121]. Definitions of healthy ageing continue to evolve. The WHO It is possible that widespread use of dietary supplements recently conceptualized a public-health framework for and fortification of the food supply in the US accounts for healthy ageing that considers physical health, mental health, the similar vitamin D status among Georgia centenarians environment, and environmental support [154]. Priorities for compared to the US population. In these Georgia centenar- action that can help achieve healthy ageing under this frame- ians, vitamin D status was higher among whites vs. African work include aligning health systems to the older population Americans, those taking dietary supplements with vitamin they now serve, developing systems of long-term care, creat- D, and those assessed in the summer or fall [70]. Seasonal ing age-friendly environments, and improving measurement, variation in vitamin D status suggests that very long-lived monitoring and understanding. This framework can also be people may retain some ability to synthesize vitamin D used to support the rapidly growing population of the very in the skin. Also, higher vitamin D status among Georgia old, such as centenarians who are aged 100 and older [140]. centenarians was significantly associated with higher grip This presentation elaborated on WHO’s framework in two strength, a measure of functional ability [50]. ways among centenarians: (1) nutrition as an environmen- Post-mortem concentrations of brain lutein in the subset tal support to healthy ageing and (2) examination of cross- of centenarians without dementia were significantly and pos- cultural differences and similarities between centenarians itively associated with a range of cognitive measures [68]. residing in Tokyo, Japan and Georgia, USA, in subjective In contrast, there were few associations of alpha-tocopherol measures of well-being, physical health, and social health. with cognitive function [68]. In summary, several biological and environmental factors Nutrition in long‑lived Georgians (USA) are associated with vitamin status throughout life includ- ing among centenarians. These factors include race/ethnic- The Georgia Centenarian Study (USA) has been ongoing ity, use of dietary supplements, food fortification, certain since 1988 and seeks to understand how centenarians live foods, and season in the case of vitamin D. Also, measuring, longer and to identify specific biological, psychological, monitoring, understanding, and modifying the nutritional sociological, and nutritional characteristics that support environment are essential for long-lived people. 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S21 or reversed, producing increases in healthy lifespan [39, 75]. Cross‑cultural differences in Japan vs. Georgia (USA) Translation of these therapies, called “geroprotectors” [110], to extend human healthspan is increasingly plausible [92, The subset of participants who were cognitively intact were the focus of these cross-cultural comparisons among cen- 113, 114]. A barrier to translation is the challenge of meas- uring changes in the rate of human ageing. tenarians in Japan compared to Georgia [111]. There were marked differences in demographic characteristics between Unlike worms, flies, and mice, humans live too long to observe complete lifespans within individual studies. Age- the Japanese and Georgia centenarians such as the percent living at home (93 vs. 80%, respectively) and living alone related disease and disability typically develop over the second half of the human life course, a period spanning (5 vs. 40%, respectively). Differences in several indices of health were also observed. Compared to the Japanese, the decades. Interventions that modify biological processes of ageing to prevent age-related disease are, therefore, needed Georgia centenarians had significantly worse cognitive func- tion and better physical function (activities of daily living), relatively early in life, before age-related disease becomes established [49, 108]. True tests of the effectiveness of such but fewer chronic diseases and better vision and hearing. The Philadelphia Geriatric Center Morale Scale was interventions will require decades of follow-up. To establish proof of concept for such long-term studies, measurements used to measure subjective well-being. Georgia centenar- ians reported higher scores on well-being (satisfaction with are needed that allow tests of a candidate therapy’s potential to slow the rate of human ageing over shorter intervals [12, social relations and psychological comfort). However, these cultural differences in well-being were attenuated after con- 73]. Measurements to quantify biological processes of ageing trolling for predictors such as sociodemographic factors and health resources. Regression analyses revealed that health could be implemented to test putative geroprotective effects of interventions over the short term. Measurements taken resources (cognitive function, hearing problems, and activi- ties of daily living) were strong predictors of well-being in before, during, and at the conclusion of an intervention could be used to estimate how that intervention might change the both countries. Social resources (living with others) were strongly associated with one dimension of well-being (atti- rate of age-dependent deterioration in system integrity, providing a simple test of whether the intervention showed tude toward one’s ageing) only among the Japanese cen- tenarians. These findings support the existing lifespan and promise to extend healthspan. Measurements to quantify biological processes of ageing are now being developed. The cross-cultural literature, indicating that declines in health impose certain limitations on adaptive capacity in oldest-old most promising combine multiple sources of information, e.g., from clinical parameters or gene expression and DNA age irrespective of cultures, and that social embeddedness is valued in Eastern cultures [111]. methylation measurements [74]. Initial epidemiologic stud- ies of these algorithm-based biomarkers of ageing indicate These cross-cultural comparisons of centenarians sug- gest that the environment differs among individuals and promise [74]. For example, so-called “epigenetic clocks” composed of dozens or hundreds of methylation marks have among cultures, especially regarding living alone or living in a nursing home, which are both high among the Georgian been shown to predict mortality in multiple studies [24]. Research is needed to test if these new ageing biomarkers compared to the Japanese centenarians. Also, findings in the Georgia centenarians suggest that nutrition may be a modi- can inform evaluations of candidate therapies to slow ageing and extend healthspan [13]. fiable environmental factor for physical function (vitamin D) and cognition (lutein). Studies are ongoing to examine Work by Belsky et al. [10–13] has focused primarily on measures of biological ageing derived from indices of organ associations of cognitive and brain health with additional nutrients in the Georgia centenarians, such as vitamin K, system functioning, including blood chemistries, blood counts, and organ system tests such as blood pressure, lung docosahexaenoic acid (DHA), and other fatty acids [68]. function, and cardiorespiratory fitness measurements. This work has yielded four main findings. First, consistent with Quantification of biological ageing: theories of biological ageing, organ systems throughout the body show age-dependent declines in integrity even among implications for clinical trials of interventions to slow ageing and extend young healthy people in their 20s and 30s. Moreover, the rate of this decline is correlated across different organ systems healthy lifespan and is variable between individuals. Thus, measurement of the rate of biological ageing in relatively young people as Interventions to extend healthy lifespan or “healthspan” are needed. Accumulating evidence suggests molecular changes the average rate of decline in integrity across organ systems is possible [11]. Second, young people whose bodies exhibit that occur with ageing are among the root causes of age- related disease and disability [80, 93]. Experiments with a faster rate of biological ageing measured in this way have worse physical functioning, as measured by tests of strength, animals show that these molecular changes can be slowed 1 3 S22 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 balance, and motor coordination, and show evidence of early Food consumption surveys are also used to evaluate the cognitive decline, as measured from changes in cognitive benefits and safety of potential supplementation and forti- test performance between childhood and midlife. They also fication strategies, as well as to inform businesses on con- report being in worse health and are rated as looking older sumer intakes, dietary impact of products and ingredients, by others [11]. Third, people with early-life characteristics as well as research and development decisions. In addition, associated with shorter healthy lifespan, including exposure the data are used for monitoring food safety via food expo- to childhood poverty and child maltreatment, poor health in sure assessments to additives, pesticides and contaminants. childhood, and low childhood cognitive function and deficits When analyzing and modelling those specific topics, it is in self-control evidence a faster rate of biological ageing of importance to have access to individual food diaries, [10]. Fourth, the rate of biological ageing measured from detailed and quality food composition or chemical data, decline in the integrity of multiple organ systems is slowed demographic, anthropometric and biomarker data. Meth- by caloric restriction, an intervention established to extend odologies for assessment of food and supplement intake healthy lifespan in animals [12]. This last study observed vary widely, however, there is a view to harmonizing them changes in the rate of biological ageing over the relatively within the European Union (EU) [2]. short term of a 2-year intervention trial. Even though the acceleration in data generation pre- Critically, Belsky et al. [10–13] observed consistent find- sents opportunities, gaps in availability or access, unfit- ings for multiple approaches to quantify biological ageing for-purpose data, lack of specific information and out- from organ system function data using their own longitudi- of-date data remain an outstanding challenge for public nal-change “Pace of Ageing” approach and cross-sectional health nutrition research. To overcome such problems, methods that compare research participants to reference data sources including market research data, online tools populations to quantify their biological age [82, 90] or their and platforms to gather data more efficiently, as well as homeostatic dysregulation [29]. These methods, which can the construction of new models combining complemen- be implemented using standard blood chemistry panels and tary data from various sources of origin can be promising other data routinely collected in clinical studies, suggest new alternatives. possibilities for studies to evaluate interventions that may Models such as the Compiled European Food Consump- affect the rate of ageing. In theory, these measures of biolog- tion Database [116] and the Global Expanded Nutrient Sup- ical ageing may be more sensitive than individual disease- ply (GENuS) Model [138] extrapolate consumption using endpoint measures, which focus on more extreme outcomes. existing databases. The Compiled European Food Consump- Instead, biological ageing measures are designed to capture tion Database estimates the consumption of the European subtle, organism-wide shifts in physiological integrity. They population using European Food Safety Authority (EFSA) may thus provide an interesting avenue for studies of nutri- comprehensive summarized intake statistics [98] and simu- tional interventions. lating 29 days of intake distributions for 40,000 individuals using 36 clusters of age groups and gender having similar diets. A limitation is that the database contains no estimates Public health nutrition in the data of nutrient intakes and no breakdown by country. Also due age: opportunities, pitfalls, and future to the applied methodology, some outliers may be over- or perspectives underestimated. The GENuS model uses Food and Agricul- tural Organization (FAO) food balance sheets, production To study healthy ageing, data-driven tools and models can and trade data combined with nutrient composition tables to be used to quantify nutrition and health in a population. calculate the nutrient supply across 175 nations, 26 demo- The value of good data can be stressed as it plays a key graphic groups and 225 food categories. The database, how- role in today’s data age, including the use of secondary data ever, does not assess consumption of foods at the individual sources. To assess intakes at a population and subpopulation level and nutrient availability is overestimated. Examples of level, the data collected need to be of high quality, while ongoing efforts to gather up-to-date and more harmonized keeping in mind time, cost, participant burden and other data on food consumption are the EU menu [2] and the Inter- factors. The opportunity to analyze specific demographics, national Dietary Data Expansion (INDDEX) project [28], including vulnerable groups from a nutritional standpoint, is but whether the databases will be accessible and how they of great importance when trying to address healthy ageing. can be used remain to be seen. Food consumption surveys provide extensive information. The use of large datasets and mathematical models They enable the assessment and monitoring of health and to assess and define optimal dietary changes in specific nutritional status of specific demographics, to inform healthy populations can generate valuable insights and opportuni- eating guidelines and to reduce diet-related chronic diseases, ties for public health nutrition strategies and food product which all have a part to play in healthy ageing. development. 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S23 Consumption of bioactive compounds can have beneficial 2025, the number of US individuals > 65 will increase by and/or adverse health effects; however, intakes of those com- 50% [150]. Globally, currently 686 million people (12%) pounds are not routinely assessed in populations. As part of the are over 60. By 2050, it is predicted that there will be nearly European Commission (EC)-funded BACCHUS, ‘Beneficial as many people aged > 60 as children under 15. In many effects of bioactive compounds in humans’ project, national countries, life expectancy of age 60 is now at least a third food consumption data were linked to bioactive composition more than what it was in the mid-twentieth century [55]. data. To estimate intake distributions and to account for vari- Interestingly, the over-80 group is projected to be the fast- ability of bioactive concentrations, a probabilistic intake mod- est growing subset in this over-65 trend, which was 14% elling approach was applied [5, 124]. in 2012, and is predicted to be at 20% in 2050 [150]. This In the EC-funded ODIN project on vitamin D entitled Food- represents a major demographic shift with significant public based solutions for optimal vitamin D nutrition and health health and socio-economic impact. Advances in science have through the life cycle; EC Contract 613977 [117], national greatly increased lifespan; however, at the same time, new food consumption surveys and a standardized vitamin D data- and developing challenges, such as sarcopenia, cardiovascu- base were combined to assess vitamin D nutrition. Incremen- lar disease, obesity, diabetes, dementia, macular degenera- tal food fortification scenarios, such as enrichment of animal tion, cataracts, and emerging infections, as well as the costs food sources (meats, eggs, fish and dairy products) were then associated with these conditions are on the rise, impact- applied to ensure the safe increase of vitamin D intakes across ing the health and functional lifespan of older adults while the population distribution and prevent deficiency. In addition, diminishing their ability to be fully contributing members safety across European countries was assessed using available of their communities. data on consumption [98] and a worst-case scenario approach Accumulating evidence, however, indicates that poor due to the lack of individual data [123]. health in late life is not inevitable. Contrary to the previously Another example examined new food products and their held belief that increased risk of diseases and disability with impact on health outcomes, such as blood pressure and car- advancing age results from inevitable, as well as genetically diovascular events, by assessing individual data on food determined intrinsic ageing processes, more recent studies consumption combined with intake models. This study by indicate that many of the usual ageing characteristics are Dainelli et al. [31] looked at the shift in intakes of potas- due to lifestyle and other modifiable factors and are not una- sium-fortified milk powder and consecutively the health voidable consequences of ageing itself [42, 51, 66]. Thus, impact via replacing milk consumption with the fortified developing strategies to increase “health span” or the years product in adults above the age of 45. of “successfully ageing” for older adults becomes critical— As part of the overall Healthy Ireland initiative [53], the socially, and economically. Irish food industry is proactively contributing to healthier Studies across species show that ageing is associated choices and product reformulation, but progress is not with dysregulated immune and inflammatory responses, assessed regularly when looking at consumption. To quan- which may contribute to many age-related diseases includ- tify the impact of voluntary food reformulation efforts on ing cancer, infection, cardiovascular diseases, diabetes, Alz- Irish consumers, probabilistic intake assessments were heimer’s disease and osteoporosis. The immune system is performed using Irish national food consumption surveys comprised of different cell types that engage in a complex (IUNA) in combination with industry data on reformulated series of interactions to defend the host against invading product composition and market share data [60–63, 122]. pathogens. These interactions, under normal conditions, are Combining databases and probabilistic intake models well-orchestrated so that a temporary upregulation in inflam- represents a great opportunity for informing public health matory responses needed to eliminate the pathogen is subse- strategies, including healthy ageing. The impact of dietary quently diminished and controlled. With ageing, the normal changes via using and modelling databases can provide pow- “checks and balances” of the immune response is impaired, erful information for government and industry; however, creating a state of chronic inflammation (hyperactivity of available and fit-for-purpose databases, as well as the tools parts of the immune system involved in innate immune and expertise to exploit such data remain a challenge. response) on one hand, and hypoactivity of the cell-mediated immunity, particularly T cells, on the other (Fig. 5). This dichotomy presents a challenge in devising effec- Public health implications tive interventions to prevent/treat age-related changes of the of immunosenescence: role of nutrition immune response. Recent evidence, however, suggests that both the hyper- and hypo-activity of immune response asso- Since January 1, 2011, every day for the next 20 years, ciated with ageing might be governed by some of the same roughly 10,000 Americans will celebrate their 65th birth- molecular/biochemical aberrations that might be responsive day. The US Census Bureau projects that between 2005 and to nutritional intervention. 1 3 S24 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 particularly the case when the focus is moved from clinical- Ageing based studies, where QoL is a traditional outcome of clinical or nutritional intervention, to the broader context of public Inflammation health. Public health implications of nutrition and QoL in the older stages of life are of paramount importance, being interconnected to all of the most prominent issues, from (1) multi-comorbidities enhanced by poor diet and nutrient de- fi T cell function ciencies, (2) polypharmacy as a consequence of the former situation and as a sign of improper approaches to healthy lifestyles, to (3) social aspects such as meal sharing with friends or families and (4) economic aspects, such as food Fig. 5 Ageing is associated with dysregulated immune and inflam- insecurity. matory responses exhibiting increased inflammation on one hand and Not only has better diet in older adults been shown to be decreased T-cell-mediated function on the other hand associated with significantly higher physical and emotional QoL scores [147] and with better functional status [45], but A significant portion of the global older population have the whole life satisfaction in older adults is impacted by nutritional problems exhibited as both under-nutrition (e.g., nutritional adequacy [79]. The definition of healthy age- micronutrient deficiencies such as B vitamins, vitamin C, ing itself includes diet quality and eating habits as essential E, D, Se, Zn, Ca, and Fe) and over-nutrition (i.e., obesity); components [121], with immediate consequences on hard often existing together [81]. These age-associated nutritional outcomes, such as overall and disease-specific mortality problems provide opportunities and challenges in developing [89]. Diet quality, which is mainly defined in terms of proper interventions that could reduce inflammation while improv - nutrient variety and adequate caloric intake, is, however, ing host defense against infection. Strategies include sin- rarely met in older adults, mostly because of the aforemen- gle nutrient interventions, e.g., vitamin E [20, 46, 48, 52, tioned issues. In particular, intake of fruits and vegetables, 56, 99, 103, 105], vitamin B6 [106], zinc [6–8, 43, 100, which provide a wide variety of different micronutrients and 126], fish oils [102, 104, 159], or whole food such as wolf- bioactive compounds, are sub-optimally consumed by older berry [38, 127, 145, 146] and pre-and probiotics [40, 87]. In people, with no improvement over the past decade. Sup- addition, calorie restriction in both animal and humans has plementation has been advocated as a valid remedy to ame- been shown to reduce inflammation and improve immune liorate diet quality challenges in older adults, most often in response [3, 101, 115, 149]. These studies provide strong a very cost-effective way. In a recent review (unpublished) evidence that appropriate nutritional intervention could opti- on the impact of reported use of the active administration of mize the immune and inflammatory responses in older adults any dietary supplement (vitamins, minerals, herb or botani- leading to improved resistance to chronic and infectious cal compounds, amino acids, dietary substances, concen- diseases. These interventions, particularly started earlier in trates, metabolites, constituents or extracts), the analysis of life, could have significant public health implications for 83,350 subjects showed reported supplement use was associ- older adults. However, success has been curbed due to the ated with a significant reduction in mortality risk for cancer lack of adequate information on specific nutritional needs of (pooled estimated HR 0.93, 95% CI 0.88–0.99) and stroke older people. As a result, older people of a wide age range (pooled estimated HR 0.97, 95% CI 0.95–0.99). A marked from 60 to 100 and with varied genetic and socio-economic impact on stroke mortality was noted for Ginkgo biloba- backgrounds are included in studies without appreciation containing supplements (HR 0.59, 95% CI 0.37–0.93), for heterogeneity of their nutritional status, which in turn, Selenium + Coenzyme Q10-containing supplements (HR reduces the effectiveness of any given intervention. Address- 0.46, 95% CI 0.33–0.64) and vitamin B (HR 0.75, 95% CI ing this gap, would expedite development of efficient and 0.62–0.91). Alternatively to a single-component analysis of cost-effective nutritional strategies to improve quality of life the effects of supplementation on health, a recent review on in older adults. Papers screened on PubMed & EmBase for trials with sample A public health perspective on nutrition size greater than 200 subjects (aged at least 50  years old, defined as and its impact on quality of life healthy or without specific diagnosis, or with most common ageing diseases—cardiovascular diseases, age-related macular degeneration, dementia or diabetes). Outcomes considered were at least one of the Despite the obvious connection existing among ageing, following outcomes: all causes mortality, CV death, major CV events nutrition and quality of life (QoL) in older adults, a sys- (composite endpoint, stroke, myocardial infarction, revascularization, tematic investigation in the field is lacking [37]. This is etc.), and cancer. 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S25 Fig. 6 Distribution of expected number of stroke events without (gray bars) and with concentrates supplementation (smoothed curves). Data are Monte Carlo microsimulations referred to the decade 2015–2025 for US fruit and vegetables concentrates and their potential impact Supplementation could thus be seen as a cost-effective solu- on risk reduction for major health events [47] showed a tion to overcome behavioral obstacles typical of older age strong inverse relationship between reported consumption yet ensuring proper intake of most relevant nutrients. and major chronic disease, in particular coronary heart dis- ease and stroke (unpublished) (Fig. 6). Thus, the potential gain in terms of events avoided due to a better nutrition, via Life in the margins: the health impact supplementation, in older adults, suggests a potential reduc- of micronutrient insufficiency tion of public health expenditure. The same simulation scenario as in the previous case Micronutrient deficiencies are common in older adults shows indeed that a significant number of cases were avoided around the globe [157]. Numerous factors can limit the (approximately 9,965,819 (95% CI 643,567–25,202,911)), ability of elders to access and consume nutrient-dense attributable to nutrient supplementation (in people aged 65 foods, such as declining income, impaired mobility, poor years or more) (Table 1). In this scenario, fostering vitamin oral health, altered taste and smell, loss of appetite, lack of consumption via fruits and vegetables or by supplementa- food variety, changes in cognition and diminished vision. tion is an essential component for promoting healthy ageing. The greatest burden of chronic disease is borne by older adults, which by their very nature can lead to a disruption of the immune system, changes in metabolism, and impact inflammatory mediators, which can increase the body’s The review focused on seven “concentrates” (juice plus—J+, need for specific micronutrients. Medications used to treat orange juice fruit and vegetable juice—FV juice, fruit juice, cherry juice, Jerusalem artichoke juice, Artichoke leaf juice). These com- chronic disease can be nutrient wasting, causing significant pounds were analyzed in terms of their impact on measurable physi- declines in the status of micronutrients vital for well-being ological outcomes (total cholesterol, homocysteine, systolic blood and health. pressure, body mass index and tumor necrosis factor alpha), widely While frank nutrient deficiency states are well-known accepted in literature as risk factors for cardiovascular NCDs. Lit- erature review results provided input for Markov chain simulation (e.g., rickets, scurvy, pellagra), there is a growing body of model, calibrated on US 2015–2025 general population, population evidence showing that less than optimal biochemical levels with metabolic syndrome and hypertension. Effect of concentrates are associated with impaired cognitive function, cardiovas- was thus simulated by linking the direct effect of each concentrate on cular disease, cancer, poor bone health, eye disease and other a clinical surrogate with the effect of the same surrogate on stroke. 1 3 S26 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 Table 1 Simulated savings in US due to the usage of supplements Age–class No supplementa- Beta-carotene C E B9 ACE tion Overall Health 65–84 403.294 (174.347; 402.078 (174.267; 360.849 399.338 391.886 (171.277; 392.184 (172.092; Care Expenditure 887.958) 871.077) (168.383; (173.627; 844.23) 821.755) (US$) 785.064) 851.128) 85 + 92.353 (40.706; 91.796 (40.695; 85.913 90.63 90.522 (40.667; 89.342 (40.482; 203.283) 199.223) (40.187; (40.564; 193.803) 192.82) 167.567) 202.015) Numbers are billions US$. Computation referred to US population 2016 and extrapolated to the decennium 2015–2025 on the estimates based on Medical Expenditure Panel Survey [54] conditions that are common in older populations [22]. The of appetite, joint pain, depression, loss of taste and smell, focus of this presentation was to examine the prevalence, cognitive impairment, and dementia [118]. Both patients and impact and risk factors for several key micronutrients in the clinicians may assume that some of these signs and symp- ageing population. toms are simply the result of ageing. Screening for B12, including methylmalonic acid (a more sensitive indicator of Vitamin B12 B12 status) should be considered in any patient experiencing these symptoms, who are vegetarian or vegan, or with long- The risk for vitamin B12 deficiency increases with age. term metformin and/or PPI use [85, 96, 120]. Using data from the National Health and Nutrition Examina- tion Survey (NHANES), 6.9% of US adults aged 51–70 years Vitamin D and 15% of those over 70 years are B12 deficient [17]. Simi- lar findings were reported in Germany, with 27.3% of peo- Optimal vitamin D status is necessary for the absorption of ple aged 65–93 having deficient serum B12 levels [30]. The calcium and phosphate required to preserve mineral homeo- decline in gastric acid secretion that occurs with advancing stasis and bone health, as well as maintaining skeletal mus- age can make it difficult to absorb food-bound B12 in meat, cle performance [26]. While hypovitaminosis D is common poultry, seafood, dairy, and eggs. For this reason, the Insti- worldwide, it is more common and severe in elders [21] tute of Medicine recommends adults over the age of 50 get due to both environmental and biological factors. Impaired their B12 from fortified foods and/or supplements [59]. mobility and residential care often limit time spent outdoors The risk for low B12 in elders may be further com- and decreased synthesis of vitamin D in the skin makes it pounded by the widespread use of proton pump inhibitors difficult to maintain adequate levels even with sun exposure. (PPI) and histamine H2 blockers, which dramatically inhibit As ageing advances, intestinal resistance to 1,25(OH)2D gastric acid secretion and the absorption of B12 [96]. A 2015 impairs the uptake of calcium and a decline in renal func- meta-analysis found an 80% increased risk of deficiency tion reduces vitamin D activation [33]. Thus, the Institute of after 10 months of regular PPI use [72]. Many older adults Medicine recommends that adults over age 70 take ≥ 800 IU are prescribed a PPI to prevent gastric bleeding secondary per day (20 µg) of vitamin D3 and increase calcium from to the use of aspirin, anticoagulants, and/or non-steroidal 1000 mg per day to 1200 mg per day for women over age anti-inflammatories. These drugs are used in the manage- 50 years and men over 70 years [58]. ment of cardiovascular disease and pain, two conditions that Osteoporosis is a silent disease and a major health con- disproportionately affect older adults. cern given the ageing of the global population. It is respon- The risk for diabetes also increases with age. Of the sible for more than 8.9 million fractures annually worldwide 30 million Americans with type-2 diabetes, 12 million are [67]. Falls are a major cause of fractures and are more com- over the age of 65 [76]. Metformin, a medication commonly mon in older adults. Roughly 30 % of people over age 65 prescribed for the treatment of type-2 diabetes, reduces fall annually, with 10–15% of these falls resulting in frac- serum B12 levels and worsens diabetes-associated neuropa- ture [77]. Sixty percent of those who fell in the previous thy [120]. Many patients taking metformin are not monitored year, will fall again [141]. Seventy-five percent of hip, spine or screened for B12 status [23]. It is not uncommon in clini- and distal forearm fractures occur among those 65 years or cal practice to see a 70-year old patient on both long-term older [97]. Fragility fractures are associated with decreased metformin and PPI. quality of life, increased disability, more frequent hospital B12 deficiency can lead to difficulty walking, tingling/ admission and an increased risk of mortality [88]. While a numbness in hands and feet, fatigue, shortness of breath, loss multimodal approach is important for fall protection, vitamin 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S27 D supplementation alone, or in combination with calcium, plague older adults: type 2 diabetes, metabolic syndrome, has been shown to significantly reduce the risk of falling in chronic inflammation, high blood pressure, atherosclerotic elders [142]. vascular disease, sudden cardiac death, osteoporosis, and A meta-analysis that included eight studies with 30,970 colon cancer [129]. Almost half (48%) of the US popula- participants conducted by the National Osteoporosis Foun- tion consumed less than the recommended amount of dietary dation found that calcium plus vitamin D supplementation magnesium in 2005–2006; down from 56% in 2001–2002 resulted in a statistically significant 15% reduced risk of total [130]. The Canadian Health Measures Survey (2012–2013), fractures and 30% reduced risk of hip fractures [148]. This found that 9.5–16.6% of Canadian adults had a serum mag- translates into large economic savings, decreased morbidity nesium below the lower reference cut-off [14]. and mortality, and improved quality of lives. Evidence from epidemiological studies, randomized con- Given the data showing the beneficial effects of vitamin trolled trials, and meta-analyses suggest an inverse associa- D on falls and fracture, it is somewhat surprising that many tion between magnesium and cardiovascular disease [132]. patients who experience a fragility fracture are not recom- A 2013 meta-analysis that included 16 studies with more mended vitamin D. In one Italian study, most patients over than 313,000 participants found higher blood levels of mag- age 65 years who had a hip fracture (98.2 and 88.3% in 2011 nesium (per 0.2 mmol/L increment) were associated with a and 2015, respectively) did not receive vitamin D supple- 30% lower risk of cardiovascular disease [34]. Magnesium mentation at the time of the fracture and only 30–35% were supplementation reduces plasma C-reactive protein (CRP) receiving vitamin D supplements 1 year after the fracture concentrations in those with levels > 3  mg/dL, which is [26]. This is unfortunate as supplementation may reduce the indicative of inflammation and an increased risk for cardio- number of subsequent fractures, enhance muscular strength, vascular disease [137]. and improve balance [25]. Magnesium is important for maintaining healthy blood Numerous medications can lead to low bone mineral den- pressure and supplementation (365–450 mg/day) has been sity and an increased risk for fracture. Statins may cause a shown to significantly lower blood pressure in those with decline in vitamin D levels and lead to smaller increases in insulin resistance, prediabetes, and other chronic diseases serum 25(OH)D concentration even with supplementation [36]. This is important given that some anti-hypertensive [18, 19]. Anticonvulsant medications accelerate vitamin D medications (e.g., thiazide diuretics) can cause hypomagne- metabolism and increase the risk for fracture [65]. Gluco- semia, decreasing their effectiveness and increasing the risk corticoids, aromatase inhibitors and androgen deprivation for heart arrhythmias [91]. treatments all significantly increase the risk for osteoporosis As mentioned previously, diabetes is a major public and fracture. The American Geriatrics Society recommends health concern, with the global prevalence increasing from against the use of PPIs for longer than 8 weeks in older 4.7% in 1980 to 8.5% in 2014, and continuing to rise [156]. adults, except in high-risk patients, due to the potential risk Insulin resistance has been shown repeatedly to decrease of bone loss, fractures and risk of Clostridium difficile infec- magnesium levels and diabetics with low magnesium show a tion [4]. more rapid disease progression and an increased risk for dia- Clinicians should assess 25(OH)D levels in those with betes-related complications. A vicious forward feeding cycle risk factors for low vitamin D, correct any deficiency, and is created. Magnesium supplementation has been shown to maintain serum levels ≥ 30 ng/mL (75 nmol/L), as recom- improve glucose metabolism and insulin sensitivity in those mended by the Endocrine Society [57]. Vitamin D supple- with type-2 diabetes [44]. mentation beyond what is currently recommended is often Certain medications can cause a decline in magnesium. necessary to correct an underlying deficiency. While the safe The Food and Drug Administration has mandated a warning upper limit for vitamin D supplementation has been set at that long-term use PPI can cause dangerously low magne- 4000 IU per day for most adults [58], clinicians generally sium levels and thiazide diuretics, often a first line treatment use 50,000 IU per week or 6000 IU per day for 8 weeks, or for hypertension, can cause a decline in magnesium, as well longer, to correct deficiency states [57]. as potassium. Dietary calcium intake should be assessed with a goal of While serum magnesium is a useful screening tool, red 1000–1200 mg per day. Patients with chronic kidney dis- blood cell magnesium testing is considered more accu- ease should be closely monitored for vitamin D and calcium rate and should be considered in patients with risk fac- intake to avoid elevated serum calcium. tors for hypomagnesemia. Magnesium supplementation (200–500 mg per day) is generally considered safe; however, Magnesium clinicians should be cautious in those with diminished renal function. Low magnesium intakes and low serum magnesium lev- Given the ageing of the global population, it is impera- els are associated with many of the chronic conditions that tive that health policy advocates, governmental officials, 1 3 S28 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 clinicians and the public be made aware of the importance of increasing age…” Although the nine subject-matter experts micronutrients in overall health, particularly in older adults. provided their insights and in some cases, laboratory-derived Clinicians must have more training in how to identify poten- data points applicable to healthy ageing, it is also evident tial nutrient dec fi iencies and what testing is most appropriate that the surface has been barely scratched and that many for determining the status of specific nutrients. We urgently additional definitions, end-points, markers of ageing can need more research to determine the “optimal” reference be proposed, and that there are likely many well-conceived range for key micronutrients in older adults, as well as mak- possible lifestyle options that can be modified to achieve ing nutrient testing more widely available, more economi- improved health and optimize the lifespan. One theme that cal, and reimbursed by insurance and government programs. resonates through this entire report is that ageing is NOT Otherwise, we will continue to see many older adults living a disease. The phrase “successful ageing” does not do jus- in the margins, when it comes to their micronutrient status. tice to the inclusive opportunity that drive an individual to While the consumption of nutrient-dense food is the foun- achieve their optimal lifespan. Quality is equally important dation for obtaining nutrients, it is simply not enough in to the quantity of life years deemed appropriate for each certain cases, such as vitamin D. Given the key role that individual, given both controllable and uncontrollable calcium and vitamin D play in maintaining bone and skel- impacting parameters. Most of the presenters either called etal muscle health, nutrient status should be more rigorously out terms such as functional ability and intrinsic capacity, evaluated by the clinician and supplementation more widely or in their oral and written contributions drew tangential recommended. With a fragility-related fracture occurring points to the health-related attributes that enable a lifespan every 3 s, this inexpensive approach should become part value option affected by the underlying physiological and of standard practice in primary and geriatric care for the psychosocial factors, health and lifestyle-related behaviors management of osteoporosis [67]. and the presence/absence of disease and rapidly-developing The widespread use of prescription drugs for the manage- decrements. Finally, the mental picture of a life course can ment of many chronic health conditions can also make it be intuitively described with adjustments in internal (genet- difficult to maintain adequate levels of specific nutrients. PPI ics) and external (environment) elements over the lifespan drugs are one of the most commonly prescribed medications affecting the slope and trajectory of a life, a progress towards and are also available over-the-counter in the United States. death that is overlaid by debilitating life stages associated The long-term use of these drugs can increase the risk of with perceptions of unhealthy and unforgiving “old age”. fracture, cause magnesium levels to plummet, and interfere Acknowledgements This conference report summarizes the presenta- with B12 absorption, as well as increasing the risk of C. tions and outcomes of the meeting entitled “Healthy Ageing: he Natural difficile infection. With the increasing prevalence of type-2 Consequences of Good Nutrition” held on December 2, 2017, in Berlin, diabetes, we will continue to see an increase in prescriptions Germany. The event was organized by the Council for Responsible Nutrition-International (http://www.crn-i.ch). The opinions expressed, for metformin, a drug known to deplete vitamin B12. While herein, are those of the authors; this conference report is not a consen- these medications can be incredibly beneficial, many older sus statement; therefore, some authors may not agree with all opinions adults are taking these drugs long term without any monitor- expressed. R. Sadana is a staff member of the World Health Organiza- ing of micronutrient status. Many clinicians are unaware of tion and contributed the section on WHO’s new mandate to measure intrinsic capacities and functional ability across the life course. All the potential for nutrient wasting associated with medication listed authors alone are responsible for the views expressed in this use and simply are not looking for it. publication and they do not necessarily represent the decisions, policy, Given that even marginal micronutrient status can or views of the World Health Organization. The section on WHO’s adversely affect muscle, joint, and eye health, as well as the new mandate to measure intrinsic capacities and functional ability across the life course draws on work by several groups and individuals, immune, cardiovascular and neurological systems, there is including John Beard, Somnath Chatterji, Alarcos Cieza, Islene Araujo an urgent need for better evidence-based guidelines, educa- de Carvalho, Ana Posarac, Jean-Pierre Michel, Jothees Amuthavalli, tion and communication with public health officials, medical Jinkook Lee, Matilde Leonardi, Gerald Stucki, Alana Officer and Anne professionals and the public. Margriet Pot. Compliance with ethical standards Conclusion Conflict of interest D.W. Belsky, D. Gregorio, M.A. Johnson, T. Low Dog, S. Meydani, S. Pigat, R. Sadana, A. Shao and J.C. Griffiths had The annual CRN-International Scientific Symposium and their travel expenses reimbursed by CRN-I. D. Marsman, T. Low Dog, subsequent conference report is continuing to explore and S. Pigat, and A. Shao are employees of their respective companies, refine scientific content related to optimal nutrition and a Procter & Gamble, Integrative Medicine Concepts, Creme Global, healthy lifespan. It is apparent that they are related, most and Amway/Nutrilite. T. Low Dog is also president of Dr. Low Dog’s Apothecary and an employee of Health Lifestyle Brands. J.C. Griffiths likely with the former affecting maximal length and achiev - is an employee of CRN-International. None of the authors declares ing a lessening of the “…decline or loss of adaptation with 1 3 European Journal of Nutrition (2018) 57 (Suppl 2):S15–S34 S29 any conflict of interest in providing their solely scientific opinion for (2017) Eleven telomere, epigenetic clock, and biomarker-com- this review. posite quantifications of biological aging: do they measure the same thing? 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European Journal of NutritionSpringer Journals

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